Grupos Investigadores

Miembros del Grupo

Líneas de Investigación

  • Cáncer de pulmón, carcinoma no microcítico de pulmón, NSCLC, carcinoma microcítico de pulmón, SCLC
  • Enfisema y carcinogénesis pulmonar
  • Investigación de biomarcadores diagnósticos, pronósticos y predictivos en cáncer de pulmón
  • Investigación en nuevas dianas terapéuticas en cáncer de pulmón

Palabras Clave

  • Células mieloides
  • Inmunolocalización
  • NSCLC
  • Pronóstico
  • Tirosin kinasas
  • Análisis multiplataforma
  • Biomarcadores
  • Biopsia líquida
  • Carcinogénesis
  • Carcinoma microcítico de pulmón
  • Carcinoma no microcítico de pulmón
  • Cribado
  • Cáncer de pulmón
  • Detección precoz
  • Exosomas
  • Inmunoterapia
  • Microambiente tumoral
  • Modelos animales
  • Modelos de riesgo
  • Modelos ortotópicos
  • Nuevas dianas terapéuticas
  • Radioterapia
  • Radiómica
  • SCLC
  • Screening
  • Tecnologías quirúrgicas mínimamente invasivas
  • Terapias dirigidas

Publicaciones Científicas desde 2018

  • Autores: Kiio, L. K. (Autor de correspondencia); Onyatta, J. O.; Ndangili, P. M.; et al.
    Revista: TALANTA
    ISSN: 0039-9140 Vol.266 N° 1 2024 págs. 124934
    Resumen
    Cancer is one of the most extensive diseases with the highest mortality rate, accounting for almost 10 million deaths in 2020. The most common cancers are breast, lung, colon and rectum and prostate cancers. Of these, lung cancer, accounted for about 1.8 million of all cancer deaths (25%) in 2020. Detection of cancer relies on presence of biomarkers such as DNA molecules, proteins and metabolites released by cancerous cells into the circulation. Carcinoembryonic antigen (CEA) is one of the biomarkers that has been used for the detection of lung cancer. However, CEA is not specific to lung cancer since it is also manifested in gastric cancer, pancreatic cancer, colorectal cancer, and breast cancer. Recently, v-YES1 Yamaguchi sarcoma viral oncogene homolog 1 (YES1) was described as a specific biomarker for lung cancer. The detection of both CEA and YES1 would give more precise and authentic information for detecting lung cancer. This is because detection of a single tumor marker usually limits the precision in tumor diagnosis, due to the fact that several cancers have more than one marker linked with their prevalence. Whereas traditional methods have been used for the detection of CEA, electrochemical immunosensors have attracted considerable attention owing to their profound advantages, including fast response, miniaturization, high selectivity, low sample requirements and magnificent sensitivity. The fabrication of a multiplex and simultaneous immunosensor is met with challenge of preparation of distinguishable immunoprobes with different redox activities. This can be addressed by incorporation of electroactive Nano metals into the sensing platform. In this study, gold nanoparticles were used for the fabrication of an ultrasensitive sandwich electrochemical multiplex immunosensor for simultaneous detection of CEA and YES1. Under optimized conditions, the electrochemical immunosensor detection limit for YES1 and CEA was found to be 0.0022 and 0.0034 ng/mL respectively within a linear range of 0.1-50 ng/mL. The proposed immunosensor proved to be stable for up to 2 weeks and had negligible cross reactivity towards various interfering compounds in human plasma. This study reports that gold nanoparticles can be bio synthesized using shade dried Mangifera indica leaves extract. The bio-synthesized gold nanoparticles coupled with thiolated protein G can be used for fabrication of a multiplex immunosensor for detection of CEA and YES1. The proposed immunosensor can provide a new approach for early diagnosis of circulating cancer biomarkers and holds great promise for application in clinical diagnosis.
  • Autores: Otegui García, Nerea Bakartxo; Houry, Maeva; Arozarena, I.; et al.
    Revista: CANCERS
    ISSN: 2072-6694 Vol.15 N° 12 2023 págs. 3076
    Resumen
    Simple Summary Immunotherapy for non-small cell lung cancer (NSCLC) is a clinical reality with impressive efficacy for some patients. However, less than half of them will benefit from this therapeutic regime, and finding indicators of response is necessary for selecting the patients likely to respond. So far, detection of PD-L1 in tumors by immunohistochemistry is the only validated predictive biomarker. In recent years, certain changes in the tumor cells (intrinsic alterations), including mutations, epigenetic changes and metabolic rewiring, have been shown to modify the type of tumor microenvironment (TME) where such a tumor grows. This TME may determine response or refractoriness to immunotherapy. Examples of key mutations are KRAS, SKT11(LKB1), KEAP1 and TP53, as well as co-mutations of these genes. Reshaping the TME with novel strategies in these particular TMEs could increase the efficacy of immunotherapy in lung cancer patients. Despite the great clinical success of immunotherapy in lung cancer patients, only a small percentage of them (<40%) will benefit from this therapy alone or combined with other strategies. Cancer cell-intrinsic and cell-extrinsic mechanisms have been associated with a lack of response to immunotherapy. The present study is focused on cancer cell-intrinsic genetic, epigenetic, transcriptomic and metabolic alterations that reshape the tumor microenvironment (TME) and determine response or refractoriness to immune checkpoint inhibitors (ICIs). Mutations in KRAS, SKT11(LKB1), KEAP1 and TP53 and co-mutations of these genes are the main determinants of ICI response in non-small-cell lung cancer (NSCLC) patients. Recent insights into metabolic changes in cancer cells that impose restrictions on cytotoxic T cells and the efficacy of ICIs indicate that targeting such metabolic restrictions may favor therapeutic responses. Other emerging pathways for therapeutic interventions include epigenetic modulators and DNA damage repair (DDR) pathways, especially in small-cell lung cancer (SCLC). Therefore, the many potential pathways for enhancing the effect of ICIs suggest that, in a few years, we will have much more personalized medicine for lung cancer patients treated with immunotherapy. Such strategies could include vaccines and chimeric antigen receptor (CAR) cells.
  • Autores: Entrialgo Cadierno, Rodrigo; Cueto Ureña, Cristina; Welch, Connor; et al.
    Revista: MOLECULAR CANCER
    ISSN: 1476-4598 Vol.22 N° 1 2023 págs. 97
  • Autores: Anfray, C.; Ummarino, A.; Calvo González, Alfonso; et al.
    Revista: METHODS IN MOLECULAR BIOLOGY
    ISSN: 1064-3745 Vol.2614 2023 págs. 93 - 108
    Resumen
    In most solid cancers, tumor-associated macrophages (TAMs) infiltrating the tumor microenvironment (TME) represent a major population of immunosuppressive cells. This correlates with poor prognosis and resistance to antitumoral therapies, including immune checkpoint inhibitors. Although initial preclinical studies were primarily meant to deplete macrophages in the TME or prevent their recruitment at tumor sites, recent evidence has indicated that the reprogramming of macrophages into cytotoxic effectors might be more beneficial in eliciting an effective antitumor immune response. Taking this into consideration, the comprehensive analysis of the phenotype and function of macrophages in the TME, and their interaction with cancer cells or other immune cells, has become of paramount importance in oncological research. Accordingly, here we explain the experimental procedures for the in vivo evaluation of tumor progression and response to therapy, with a particular focus on the detailed analysis of TAMs and related immune cells in the TME by flow cytometry, RNA analysis, and multiplex immunophenotyping. The output generated through these experiments allow researchers to test the efficacy of new therapeutic strategies on targeting.
  • Autores: Muley, H.; Valencia Leoz, Karmele; Casas, J.; et al.
    Revista: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
    ISSN: 1422-0067 Vol.24 N° 2 2023 págs. 946
    Resumen
    Breast cancer (BC) is the most common malignancy in women worldwide. While the main systemic treatment option is anthracycline-containing chemotherapy, chemoresistance continues to be an obstacle to patient survival. Carnitine palmitoyltransferase 1C (CPT1C) has been described as a poor-prognosis marker for several tumour types, as it favours tumour growth and hinders cells from entering senescence. At the molecular level, CPT1C has been associated with lipid metabolism regulation and important lipidome changes. Since plasma membrane (PM) rigidity has been associated with reduced drug uptake, we explored whether CPT1C expression could be involved in PM remodelling and drug chemoresistance. Liquid chromatography-high resolution mass spectrometry (LC-HRMS) lipid analysis of PM-enriched fractions of MDA-MB-231 BC cells showed that CPT1C silencing increased PM phospholipid saturation, suggesting a rise in PM rigidity. Moreover, CPT1C silencing increased cell survival against doxorubicin (DOX) treatment in different BC cells due to reduced drug uptake. These findings, further complemented by ROC plotter analysis correlating lower CPT1C expression with a lower pathological complete response to anthracyclines in patients with more aggressive types of BC, suggest CPT1C as a novel predictive biomarker for BC chemotherapy.
  • Autores: Moez, E. K.; Warkentin, M. T.; Brhane, Y.; et al.
    Revista: JOURNAL OF THE NATIONAL CANCER INSTITUTE
    ISSN: 0027-8874 Vol.115 N° 9 2023 págs. 1060 - 1070
    Resumen
    Background Although lung cancer screening with low-dose computed tomography is rolling out in many areas of the world, differentiating indeterminate pulmonary nodules remains a major challenge. We conducted one of the first systematic investigations of circulating protein markers to differentiate malignant from benign screen-detected pulmonary nodules. Methods Based on 4 international low-dose computed tomography screening studies, we assayed 1078 protein markers using prediagnostic blood samples from 1253 participants based on a nested case-control design. Protein markers were measured using proximity extension assays, and data were analyzed using multivariable logistic regression, random forest, and penalized regressions. Protein burden scores (PBSs) for overall nodule malignancy and imminent tumors were estimated. Results We identified 36 potentially informative circulating protein markers differentiating malignant from benign nodules, representing a tightly connected biological network. Ten markers were found to be particularly relevant for imminent lung cancer diagnoses within 1 year. Increases in PBSs for overall nodule malignancy and imminent tumors by 1 standard deviation were associated with odds ratios of 2.29 (95% confidence interval: 1.95 to 2.72) and 2.81 (95% confidence interval: 2.27 to 3.54) for nodule malignancy overall and within 1 year of diagnosis, respectively. Both PBSs for overall nodule malignancy and for imminent tumors were substantially higher for those with malignant nodules than for those with benign nodules, even when limited to Lung Computed Tomography Screening Reporting and Data System (LungRADS) category 4 (P < .001). Conclusions Circulating protein markers can help differentiate malignant from benign pulmonary nodules. Validation with an independent computed tomographic screening study will be required before clinical implementation.
  • Autores: Cross, A. R.; De Andrea, Carlos Eduardo; Villalba Esparza, María; et al.
    Revista: JCI INSIGHT
    ISSN: 2379-3708 Vol.8 N° 2 2023 págs. e157837
    Resumen
    Severe lung damage resulting from COVID-19 involves complex interactions between diverse populations of immune and stromal cells. In this study, we used a spatial transcriptomics approach to delineate the cells, pathways, and genes present across the spectrum of histopathological damage in COVID-19-affected lung tissue. We applied correlation network-based approaches to deconvolve gene expression data from 46 areas of interest covering more than 62,000 cells within well-preserved lung samples from 3 patients. Despite substantial interpatient heterogeneity, we discovered evidence for a common immune-cell signaling circuit in areas of severe tissue that involves crosstalk between cytotoxic lymphocytes and pro-inflammatory macrophages. Expression of IFNG by cytotoxic lymphocytes was associated with induction of chemokines, including CXCL9, CXCL10, and CXCL11, which are known to promote the recruitment of CXCR3+ immune cells. The TNF superfamily members BAFF (TNFSF13B) and TRAIL (TNFSF10) were consistently upregulated in the areas with severe tissue damage. We used published spatial and single-cell SARS-CoV-2 data sets to validate our findings in the lung tissue from additional cohorts of patients with COVID-19. The resulting model of severe COVID-19 immune-mediated tissue pathology may inform future therapeutic strategies.
  • Autores: Lee, S.; Martínez-Valbuena, I.; De Andrea, Carlos Eduardo; et al.
    Revista: ANNALS OF NEUROLOGY
    ISSN: 0364-5134 Vol.93 N° 3 2023 págs. 431 - 445
    Resumen
    Objective: Progressive supranuclear palsy (PSP) is a 4R-tauopathy showing heterogeneous tau cytopathology commencing in the globus pallidus (GP) and the substantia nigra (SN), regions also associated with age-related iron accumulation. Abnormal iron levels have been extensively associated with tau pathology in neurodegenerative brains, however, its role in PSP pathogenesis remains yet unknown. We perform the first cell type-specific evaluation of PSP iron homeostasis and the closely related oxygen homeostasis, in relation to tau pathology in human postmortem PSP brains. Methods: In brain regions vulnerable to PSP pathology (GP, SN, and putamen), we visualized iron deposition in tau-affected and unaffected neurons, astroglia, oligodendrocytes, and microglia, using a combination of iron staining with immunolabelling. To further explore molecular pathways underlying our observations, we examined the expression of key iron and oxygen homeostasis mRNA transcripts and proteins. Results: We found astrocytes as the major cell type accumulating iron in the early affected regions of PSP, highly associated with cellular tau pathology. The same regions are affected by dysregulated expression of alpha and beta hemoglobin and neuroglobin showing contrasting patterns. We discovered changes in iron and oxygen homeostasis-related gene expression associated with aging of the brain, and identified dysregulated expression of rare neurodegeneration with brain iron accumulation (NBIA) genes associated with tau pathology to distinguish PSP from the healthy aging brain. Interpretation: We present novel aspects of PSP pathophysiology highlighting an overlap with NBIA pathways. Our findings reveal potential novel targets for therapy development and have implications beyond PSP for other iron-associated neurodegenerative diseases.
  • Autores: Anthiya, S.; Öztürk, S. C.; Yanik, H.; et al.
    Revista: JOURNAL OF CONTROLLED RELEASE
    ISSN: 0168-3659 Vol.357 2023 págs. 67 - 83
    Resumen
    K-RAS is a highly relevant oncogene that is mutated in approximately 90% of pancreatic cancers and 20-25% of lung adenocarcinomas. The aim of this work was to develop a new anti-KRAS siRNA therapeutic strategy through the engineering of functionalized lipid nanoparticles (LNPs). To do this, first, a potent pan anti-KRAS siRNA sequence was chosen from the literature and different chemical modifications of siRNA were tested for their transfection efficacy (KRAS knockdown) and anti-proliferative effects on various cancer cell lines. Second, a selected siRNA candidate was loaded into tLyp-1 targeted and non-targeted lipid nanoparticles (LNPs). The biodistribution and antitumoral efficacy of selected siRNA-loaded LNP-prototypes were evaluated in vivo using a pancreatic cancer murine model (subcutaneous xenograft CFPAC-1 tumors). Our results show that tLyp-1-tagged targeted LNPs have an enhanced accumulation in the tumor compared to non-targeted LNPs. Moreover, a sig-nificant reduction in the pancreatic tumor growth was observed when the anti-KRAS siRNA treatment was combined with a classical chemotherapeutic agent, gemcitabine. In conclusion, our work demonstrates the benefits of using a targeting approach to improve tumor accumulation of siRNA-LNPs and its positive impact on tumor reduction.
  • Autores: Lasheras-Otero, I.; Feliu, I.; Maillo, A.; et al.
    Revista: JOURNAL OF INVESTIGATIVE DERMATOLOGY
    ISSN: 0022-202X Vol.143 N° 2 2023 págs. 305 - 316.e5
    Resumen
    Circulating tumor cells are the key link between a primary tumor and distant metastases, but once in the bloodstream, loss of adhesion induces cell death. To identify the mechanisms relevant for melanoma circulating tumor cell survival, we performed RNA sequencing and discovered that detached melanoma cells and isolated melanoma circulating tumor cells rewire lipid metabolism by upregulating fatty acid (FA) transport and FA beta-oxidation-related genes. In patients with melanoma, high expression of FA transporters and FA beta-oxidation enzymes significantly correlates with reduced progression-free and overall survival. Among the highest expressed regulators in melanoma circulating tumor cells were the carnitine transferases carnitine O-octanoyl-transferase and carnitine acetyltransferase, which control the shuttle of peroxisome-derived medium-chain FAs toward mitochondria to fuel mitochondrial FA beta-oxidation. Knockdown of carnitine O-octanoyltransferase or carnitine acetyltransferase and short-term treatment with peroxisomal or mitochondrial FA beta-oxidation in-hibitors thioridazine or ranolazine suppressed melanoma metastasis in mice. Carnitine O-octanoyltransferase and carnitine acetyltransferase depletion could be rescued by medium-chain FA supplementation, indicating that the peroxisomal supply of FAs is crucial for the survival of nonadherent melanoma cells. Our study identifies targeting the FA-based cross-talk between peroxisomes and mitochondria as a potential therapeutic opportunity to challenge melanoma progression. Moreover, the discovery of the antimetastatic activity of the Food and Drug Administration-approved drug ranolazine carries translational potential.
  • Autores: Robbins, H. A. (Autor de correspondencia); Alcala, K.; Moez, E. K.; et al.
    Revista: ANNALS OF EPIDEMIOLOGY
    ISSN: 1047-2797 Vol.77 2023 págs. 1 - 12
    Resumen
    The Integrative Analysis of Lung Cancer Etiology and Risk (INTEGRAL) program is an NCI-funded initiative with an objective to develop tools to optimize low-dose CT (LDCT) lung cancer screening. Here, we de-scribe the rationale and design for the Risk Biomarker and Nodule Malignancy projects within INTEGRAL. The overarching goal of these projects is to systematically investigate circulating protein markers to include on a panel for use (i) pre-LDCT, to identify people likely to benefit from screening, and (ii) post-LDCT, to differentiate benign versus malignant nodules. To identify informative proteins, the Risk Biomarker project measured 1161 proteins in a nested-case control study within 2 prospective cohorts (n = 252 lung cancer cases and 252 controls) and replicated associations for a subset of proteins in 4 cohorts (n = 479 cases and 479 controls). Eligible participants had a current or former history of smok-ing and cases were diagnosed up to 3 years following blood draw. The Nodule Malignancy project mea-sured 1078 proteins among participants with a heavy smoking history within four LDCT screening stud-ies (n = 425 cases diagnosed up to 5 years following blood draw, 430 benign-nodule controls, and 398 nodule-free controls).The INTEGRAL panel will enable absolute quantification of 21 proteins. We will evaluate its perfor-mance in the Risk Biomarker project using a case-cohort study including 14 cohorts (n = 1696 cases and 2926 subcohort representatives), and in the Nodule Malignancy project within five LDCT screening studies (n = 675 cases, 680 benign-nodule controls, and 648 nodule-free controls). Future progress to advance lung cancer early detection biomarkers will require carefully designed validation, translational, and comparative studies.
  • Autores: Macaya Erro, Irati; Román Moreno, Marta; Welch, Connor; et al.
    Revista: NATURE COMMUNICATIONS
    ISSN: 2041-1723 Vol.14 N° 1 2023 págs. 6332
    Resumen
    Drug combinations are key to circumvent resistance mechanisms compromising response to single anti-cancer targeted therapies. The implementation of combinatorial approaches involving MEK1/2 or KRASG12C inhibitors in the context of KRAS-mutated lung cancers focuses fundamentally on targeting KRAS proximal activators or effectors. However, the antitumor effect is highly determined by compensatory mechanisms arising in defined cell types or tumor subgroups. A potential strategy to find drug combinations targeting a larger fraction of KRAS-mutated lung cancers may capitalize on the common, distal gene expression output elicited by oncogenic KRAS. By integrating a signature-driven drug repurposing approach with a pairwise pharmacological screen, here we show synergistic drug combinations consisting of multi-tyrosine kinase PKC inhibitors together with MEK1/2 or KRASG12C inhibitors. Such combinations elicit a cytotoxic response in both in vitro and in vivo models, which in part involves inhibition of the PKC inhibitor target AURKB. Proteome profiling links dysregulation of MYC expression to the effect of both PKC inhibitor-based drug combinations. Furthermore, MYC overexpression appears as a resistance mechanism to MEK1/2 and KRASG12C inhibitors. Our study provides a rational framework for selecting drugs entering combinatorial strategies and unveils MEK1/2- and KRASG12C-based therapies for lung cancer.
  • Autores: Valencia Leoz, Karmele; Montuenga Badía, Luis; Calvo González, Alfonso
    Revista: CLINICAL CANCER RESEARCH
    ISSN: 1078-0432 Vol.29 N° 19 2023 págs. 3832 - 3834
    Resumen
    The influence of sex on immunotherapy response in patients with non-small cell lung cancer (NSCLC) had been studied with no clear conclusions. An article in this issue reports that a key determinant of response is not sex but the existence of a 17ß-estradiol/ER¿/PDL1 signaling loop in NSCLC. This intriguing result opens new therapeutic options. See related article by Anobile et al., p. 3958.
  • Autores: Calvisi, D.; Boulter, L.; Vaquero, J.; et al.
    Revista: NATURE REVIEWS GASTROENTEROLOGY AND HEPATOLOGY
    ISSN: 1759-5045 Vol.20 N° 7 2023 págs. 462 - 480
    Resumen
    Preclinical research is required to improve our understanding of cholangiocarcinoma (CCA). In this Consensus Statement, a task force of experts provides recommendations on the criteria for preclinical models of CCA to increase disease understanding and help to develop novel therapeutic approaches. Cholangiocarcinoma (CCA) is a rare malignancy that develops at any point along the biliary tree. CCA has a poor prognosis, its clinical management remains challenging, and effective treatments are lacking. Therefore, preclinical research is of pivotal importance and necessary to acquire a deeper understanding of CCA and improve therapeutic outcomes. Preclinical research involves developing and managing complementary experimental models, from in vitro assays using primary cells or cell lines cultured in 2D or 3D to in vivo models with engrafted material, chemically induced CCA or genetically engineered models. All are valuable tools with well-defined advantages and limitations. The choice of a preclinical model is guided by the question(s) to be addressed; ideally, results should be recapitulated in independent approaches. In this Consensus Statement, a task force of 45 experts in CCA molecular and cellular biology and clinicians, including pathologists, from ten countries provides recommendations on the minimal criteria for preclinical models to provide a uniform approach. These recommendations are based on two rounds of questionnaires completed by 35 (first round) and 45 (second round) experts to reach a consensus with 13 statements. An agreement was defined when at least 90% of the participants voting anonymously agreed with a statement. The ultimate goal was to transfer basic laboratory research to the clinics through increased disease understanding and to develop clinical biomarkers and innovative therapies for patients with CCA.
  • Autores: Expósito Rincón, Francisco; Redrado Jordán, Miriam; Houry, Maeva; et al.
    Revista: CANCER RESEARCH
    ISSN: 0008-5472 Vol.83 N° 15 2023 págs. 2513 - 2526
    Resumen
    Immunotherapy resistance in non-small cell lung cancer (NSCLC) may be mediated by an immunosuppressive microenvironment, which can be shaped by the mutational landscape of the tumor. Here, we observed genetic alterations in the PTEN/PI3K/AKT/mTOR pathway and/or loss of PTEN expression in >25% of patients with NSCLC, with higher frequency in lung squamous carcinomas (LUSC). Patients with PTEN-low tumors had higher levels of PD-L1 and PD-L2 and showed worse progression-free survival when treated with immunotherapy. Development of a Pten-null LUSC mouse model revealed that tumors with PTEN loss were refractory to antiprogrammed cell death protein 1 (anti-PD-1), highly metastatic and fibrotic, and secreted TGFß/CXCL10 to promote conversion of CD4+ lymphocytes into regulatory T cells (Treg). Human and mouse PTEN-low tumors were enriched in Tregs and expressed higher levels of immunosuppressive genes. Importantly, treatment of mice bearing Pten-null tumors with TLR agonists and anti-TGFß antibody aimed to alter this immunosuppressive microenvironment and led to tumor rejection and immunologic memory in 100% of mice. These results demonstrate that lack of PTEN causes immunotherapy resistance in LUSCs by establishing an immunosuppressive tumor microenvironment that can be reversed therapeutically. Significance: PTEN loss leads to the development of an immunosuppressive microenvironment in lung cancer that confers resistance to anti-PD-1 therapy, which can be overcome by targeting PTEN loss-mediated immunosuppression.
  • Autores: Bocanegra, A. (Autor de correspondencia); Fernández Hinojal, Gonzalo; Ajona Martínez-Polo, Daniel; et al.
    Revista: EMBO REPORTS
    ISSN: 1469-221X Vol.24 N° 8 2023 págs. e55884
    Resumen
    Recent studies highlight the importance of baseline functional immunity for immune checkpoint blockade therapies. High-dimensional systemic immune profiling is performed in a cohort of non-small-cell lung cancer patients undergoing PD-L1/PD-1 blockade immunotherapy. Responders show high baseline myeloid phenotypic diversity in peripheral blood. To quantify it, we define a diversity index as a potential biomarker of response. This parameter correlates with elevated activated monocytic cells and decreased granulocytic phenotypes. High-throughput profiling of soluble factors in plasma identifies fractalkine (FKN), a chemokine involved in immune chemotaxis and adhesion, as a biomarker of response to immunotherapy that also correlates with myeloid cell diversity in human patients and murine models. Secreted FKN inhibits lung adenocarcinoma growth in vivo through a prominent contribution of systemic effector NK cells and increased tumor immune infiltration. FKN sensitizes murine lung cancer models refractory to anti-PD-1 treatment to immune checkpoint blockade immunotherapy. Importantly, recombinant FKN and tumor-expressed FKN are efficacious in delaying tumor growth in vivo locally and systemically, indicating a potential therapeutic use of FKN in combination with immunotherapy.
  • Autores: Entrialgo Cadierno, Rodrigo; Cueto Ureña, Cristina; Welch, Connor; et al.
    Revista: MOLECULAR CANCER
    ISSN: 1476-4598 Vol.22 N° 1 2023 págs. 86
    Resumen
    BackgroundThe discovery of functionally relevant KRAS effectors in lung and pancreatic ductal adenocarcinoma (LUAD and PDAC) may yield novel molecular targets or mechanisms amenable to inhibition strategies. Phospholipids availability has been appreciated as a mechanism to modulate KRAS oncogenic potential. Thus, phospholipid transporters may play a functional role in KRAS-driven oncogenesis. Here, we identified and systematically studied the phospholipid transporter PITPNC1 and its controlled network in LUAD and PDAC.MethodsGenetic modulation of KRAS expression as well as pharmacological inhibition of canonical effectors was completed. PITPNC1 genetic depletion was performed in in vitro and in vivo LUAD and PDAC models. PITPNC1-deficient cells were RNA sequenced, and Gene Ontology and enrichment analyses were applied to the output data. Protein-based biochemical and subcellular localization assays were run to investigate PITPNC1-regulated pathways. A drug repurposing approach was used to predict surrogate PITPNC1 inhibitors that were tested in combination with KRASG12C inhibitors in 2D, 3D, and in vivo models.ResultsPITPNC1 was increased in human LUAD and PDAC, and associated with poor patients' survival. PITPNC1 was regulated by KRAS through MEK1/2 and JNK1/2. Functional experiments showed PITPNC1 requirement for cell proliferation, cell cycle progression and tumour growth. Furthermore, PITPNC1 overexpression enhanced lung colonization and liver metastasis. PITPNC1 regulated a transcriptional signature which highly overlapped with that of KRAS, and controlled mTOR localization via enhanced MYC protein stability to prevent autophagy. JAK2 inhibitors were predicted as putative PITPNC1 inhibitors with antiproliferative effect and their combination with KRASG12C inhibitors elicited a substantial anti-tumour effect in LUAD and PDAC.ConclusionsOur data highlight the functional and clinical relevance of PITPNC1 in LUAD and PDAC. Moreover, PITPNC1 constitutes a new mechanism linking KRAS to MYC, and controls a druggable transcriptional network for combinatorial treatments.
  • Autores: Felberg, A.; Bienkowski, M.; Stokowy, T.; et al.
    Revista: IMMUNOBIOLOGY
    ISSN: 0171-2985 Vol.228 N° 5 2023 págs. 51 - 52
  • Autores: Herrera-Campos, A. B.; Zamudio-Martínez, E.; Delgado-Bellido, D.; et al.
    Revista: CANCERS
    ISSN: 2072-6694 Vol.14 N° 11 2022 págs. 2740
    Resumen
    Simple Summary The local conditions of tumor cell growth, known as the tumor microenvironment (TME), are characterized by low oxygen supply (hypoxia) caused by insufficient blood delivery. Hypoxic cancers have a strong invasive potential, metastasis, resistance to therapy, and a poor clinical prognosis. The use of supplemental oxygen, known as hyperoxia, has been described to diminish the hypoxic state and to achieve a better response to different treatments. Here, we provide an overview of how hyperoxia interacts with other therapies decreasing tumor progression and the negative effects of the use of high oxygen levels. We also perform an analysis, showing the differences in the patterns of expression between a tumor-derived cell line and a nonmalignant cell line. Hyperoxia is used in order to counteract hypoxia effects in the TME (tumor microenvironment), which are described to boost the malignant tumor phenotype and poor prognosis. The reduction of tumor hypoxic state through the formation of a non-aberrant vasculature or an increase in the toxicity of the therapeutic agent improves the efficacy of therapies such as chemotherapy. Radiotherapy efficacy has also improved, where apoptotic mechanisms seem to be implicated. Moreover, hyperoxia increases the antitumor immunity through diverse pathways, leading to an immunopermissive TME. Although hyperoxia is an approved treatment for preventing and treating hypoxemia, it has harmful side-effects. Prolonged exposure to high oxygen levels may cause acute lung injury, characterized by an exacerbated immune response, and the destruction of the alveolar-capillary barrier. Furthermore, under this situation, the high concentration of ROS may cause toxicity that will lead not only to cell death but also to an increase in chemoattractant and proinflammatory cytokine secretion. This would end in a lung leukocyte recruitment and, therefore, lung damage. Moreover, unregulated inflammation causes different consequences promoting tumor development and metastasis. This process is known as protumor inflammation, where different cell types and molecules are implicated; for instance, IL-1 beta has been described as a key cytokine. Although current results show benefits over cancer therapies using hyperoxia, further studies need to be conducted, not only to improve tumor regression, but also to prevent its collateral damage.
  • Autores: Garmendia Iturbe, Irati; Redín Cabodevilla, María Esther; Montuenga Badía, Luis; et al.
    Revista: MOLECULAR CANCER THERAPEUTICS
    ISSN: 1535-7163 Vol.21 N° 9 2022 págs. 1371 - 1380
    Resumen
    YES1 is a nonreceptor tyrosine kinase that belongs to the SRC family of kinases (SFK) and controls multiple cancer signaling pathways. YES1 is amplified and overexpressed in many tumor types, where it promotes cell proliferation, survival, and invasive-ness. Therefore, YES1 has been proposed as an emerging target in solid tumors. In addition, studies have shown that YES1 is a prognostic biomarker and a predictor of dasatinib activity. Several SFKs-targeting drugs have been developed, and some of them have reached clinical trials. However, these drugs have encountered challenges to their utilization in the clinical practice in unselected patients due to toxicity and lack of efficacy. In the case of YES1, novel specific inhibitors have been developed and tested in pre -clinical models, with impressive antitumor effects. In this review, we summarize the structure and activation of YES1 and describe its role in cancer as a target and prognostic and companion biomarker. We also address the efficacy of SFKs inhibitors that are currently in clinical trials, highlighting the main hindrances for their clinical use. Current available information strongly suggests that inhibiting YES1 in tumors with high expression of this protein is a promising strategy against cancer.
  • Autores: Carmona de la Torre, Francisco de Asís; Mínguez-Olaondo, A. (Autor de correspondencia); López-Bravo, A.; et al.
    Revista: FRONTIERS IN NEUROLOGY
    ISSN: 1664-2295 Vol.13 2022 págs. 886609
    Resumen
    IntroductionOn March 11, 2020, the World Health Organization sounded the COVID-19 pandemic alarm. While efforts in the first few months focused on reducing the mortality of infected patients, there is increasing data on the effects of long-term infection (Post-COVID-19 condition). Among the different symptoms described after acute infection, those derived from autonomic dysfunction are especially frequent and limiting. ObjectiveTo conduct a narrative review synthesizing current evidence of the signs and symptoms of dysautonomia in patients diagnosed with COVID-19, together with a compilation of available treatment guidelines. ResultsAutonomic dysfunction associated with SARS-CoV-2 infection occurs at different temporal stages. Some of the proposed pathophysiological mechanisms include direct tissue damage, immune dysregulation, hormonal disturbances, elevated cytokine levels, and persistent low-grade infection. Acute autonomic dysfunction has a direct impact on the mortality risk, given its repercussions on the respiratory, cardiovascular, and neurological systems. Iatrogenic autonomic dysfunction is a side effect caused by the drugs used and/or admission to the intensive care unit. Finally, late dysautonomia occurs in 2.5% of patients with Post-COVID-19 condition. While orthostatic hypotension and neurally-mediated syncope should be considered, postural orthostatic tachycardia syndrome (POTS) appears to be the most common autonomic phenotype among these patients. A review of diagnostic and treatment guidelines focused on each type of dysautonomic condition was done. ConclusionSymptoms deriving from autonomic dysfunction involvement are common in those affected by COVID-19. These symptoms have a great impact on the quality of life both in the short and medium to long term. A better understanding of the pathophysiological mechanisms of Post-COVID manifestations that affect the autonomic nervous system, and targeted therapeutic management could help reduce the sequelae of COVID-19, especially if we act in the earliest phases of the disease.
  • Autores: Torres-Andón, F.; Leon Valencia, Sergio; Ummarino, A.; et al.
    Revista: BIOMEDICINES
    ISSN: 2227-9059 Vol.10 N° 7 2022 págs. 1590
    Resumen
    Toll-like receptors (TLRs) are natural initial triggers of innate and adaptive immune responses. With the advent of cancer immunotherapy, nucleic acids engineered as ligands of endosomal TLRs have been investigated for the treatment of solid tumors. Despite promising results, their systemic administration, similarly to other immunotherapies, raises safety issues. To overcome these problems, recent studies have applied the direct injection of endosomal TLR agonists in the tumor and/or draining lymph nodes, achieving high local drug exposure and strong antitumor response. Importantly, intratumoral delivery of TLR agonists showed powerful effects not only against the injected tumors but also often against uninjected lesions (abscopal effects), resulting in some cases in cure and antitumoral immunological memory. Herein, we describe the structure and function of TLRs and their role in the tumor microenvironment. Then, we provide our vision on the potential of intratumor versus systemic delivery or vaccination approaches using TLR agonists, also considering the use of nanoparticles to improve their targeting properties. Finally, we collect the preclinical and clinical studies applying intratumoral injection of TLR agonists as monotherapies or in combination with: (a) other TLR or STING agonists; (b) other immunotherapies; (c) radiotherapy or chemotherapy; (d) targeted therapies.
  • Autores: Murthy, P. K. L. (Autor de correspondencia); Xi, R.; Arguijo, D.; et al.
    Revista: DEVELOPMENTAL CELL
    ISSN: 1534-5807 Vol.57 N° 3 2022 págs. 310 - +
    Resumen
    Oncogenic Kras induces a hyper-proliferative state that permits cells to progress to neoplasms in diverse epithelial tissues. Depending on the cell of origin, this also involves lineage transformation. Although a multitude of downstream factors have been implicated in these processes, the precise chronology of molecular events controlling them remains elusive. Using mouse models, primary human tissues, and cell lines, we show that, in Kras-mutant alveolar type II cells (AEC2), FOSL1-based AP-1 factor guides the mSWI/SNF complex to increase chromatin accessibility at genomic loci controlling the expression of genes necessary for neoplastic transformation. We identified two orthogonal processes in Kras-mutant distal airway club cells. The first promoted their transdifferentiation into an AEC2-like state through NKX2.1, and the second controlled oncogenic transformation through the AP-1 complex. Our results suggest that neoplasms retain an epigenetic memory of their cell of origin through cell-type-specific transcription factors. Our analysis showed that a cross tissue-conserved AP-1-dependent chromatin remodeling program regulates carcinogenesis.
  • Autores: Palanca-Ballester, C.; Hervas, D.; Villalba Esparza, María; et al.
    Revista: CLINICAL EPIGENETICS (PRINT)
    ISSN: 1868-7075 Vol.14 N° 1 2022 págs. 116
    Resumen
    Lung cancer patients are diagnosed at late stages when curative treatments are no longer possible; thus, molecular biomarkers for noninvasive detection are urgently needed. In this sense, we previously identified and validated an epigenetic 4-gene signature that yielded a high diagnostic performance in tissue and invasive pulmonary fluids. We analyzed DNA methylation levels using the ultrasensitive digital droplet PCR in noninvasive samples in a cohort of 83 patients. We demonstrated that BCAT1 is the candidate that achieves high diagnostic efficacy in circulating DNA derived from plasma (area under the curve: 0.85). Impact of potentially confounding variables was also explored.
  • Autores: Redín Cabodevilla, María Esther; Garrido-Martín, E. M.; Valencia Leoz, Karmele; et al.
    Revista: JOURNAL OF THORACIC ONCOLOGY
    ISSN: 1556-0864 Vol.17 N° 12 2022 págs. 1387 - 1403
    Resumen
    Introduction: SCLC is an extremely aggressive subtype of lung cancer without approved targeted therapies. Here we identified YES1 as a novel targetable oncogene driving SCLC maintenance and metastasis.Methods: Association between YES1 levels and prognosis was evaluated in SCLC clinical samples. In vitro functional experiments for proliferation, apoptosis, cell cycle, and cytotoxicity were performed. Genetic and pharmacologic inhibition of YES1 was evaluated in vivo in cell-and patient -derived xenografts and metastasis. YES1 levels were eval-uated in mouse and patient plasma-derived exosomes.Results: Overexpression or gain/amplification of YES1 was identified in 31% and 26% of cases, respectively, across molecular subgroups, and was found as an independent predictor of poor prognosis. Genetic depletion of YES1 dramatically reduced cell proliferation, three-dimensional organoid formation, tumor growth, and distant metastasis, leading to extensive apoptosis and tumor regressions. Mechanistically, YES1-inhibited cells revealed alterations in the replisome and DNA repair processes, that conferred sensitivity to irradiation. Pharmacologic blockade with the novel YES1 inhibitor CH6953755 or dasatinib induced marked antitumor activity in organoid models and cell-and patient-derived xenografts. YES1 protein was detected in plasma exosomes from patients and mouse models, with levels matching those of tumors, suggesting that circulating YES1 could represent a biomarker for patient selection/ monitoring.Conclusions: Our results provide evidence that YES1 is a new druggable oncogenic target and biomarker to advance the clinical management of a subpopulation of patients with SCLC.
  • Autores: Robles-Valero, J.; Fernández-Nevado, L.; Cuadrado, M.; et al.
    Revista: MOLECULAR ONCOLOGY
    ISSN: 1574-7891 Vol.16 N° 19 2022 págs. 3533 - 3553
    Resumen
    Mutations in the VAV1 guanine nucleotide exchange factor 1 have been recently found in peripheral T cell lymphoma and nonsmall-cell lung cancer (NSCLC). To understand their pathogenic potential, we generated a gene-edited mouse model that expresses a VAV1 mutant protein that recapitulates the signalling alterations present in the VAV1 mutant subclass most frequently found in tumours. We could not detect any overt tumourigenic process in those mice. However, the concurrent elimination of the Trp53 tumour suppressor gene in them drives T cell lymphomagenesis. This process represents an exacerbation of the normal functions that wild-type VAV1 plays in follicular helper T cells. We also found that, in combination with the Kras oncogene, the VAV1 mutant version favours progression of NSCLC. These data indicate that VAV1 mutations play critical, although highly cell-type-specific, roles in tumourigenesis. They also indicate that such functions are contingent on the mutational landscape of the tumours involved.
  • Autores: Moutafi, M. K.; Molero, M.; Martínez-Morilla, S.; et al.
    Revista: JOURNAL FOR IMMUNOTHERAPY OF CANCER
    ISSN: 2051-1426 Vol.10 N° 8 2022 págs. e004757
    Resumen
    Background Most patients with advanced non-small-cell lung cancer (NSCLC) fail to derive significant benefit from programmed cell death protein-1 (PD-1) axis blockade, and new biomarkers of response are needed. In this study, we aimed to discover and validate spatially resolved protein markers associated with sensitivity to PD-1 axis inhibition in NSCLC. Methods We initially assessed a discovery cohort of 56 patients with NSCLC treated with PD-1 axis inhibitors at Yale Cancer Center. Using the GeoMx Digital Spatial Profiling (DSP) system, 71 proteins were measured in spatial context on each spot in a tissue microarray. We used the AQUA method of quantitative immunofluorescence (QIF) to orthogonally validate candidate biomarkers. For external independent validation, we assessed whole tissue sections derived from 128 patients with NSCLC treated with single-agent PD-1 axis inhibitors at the 12 de Octubre Hospital (Madrid) using DSP. We further analyzed two immunotherapy untreated cohorts to address prognostic significance (n=252 from Yale Cancer Center; n=124 from University Clinic of Navarra) using QIF and DSP, respectively. Results Using continuous log-scaled data, we identified CD44 expression in the tumor compartment (pan-cytokeratin (CK)+) as a novel predictor of prolonged progression-free survival (PFS) (multivariate HR=0.68, p=0.043) in the discovery set. We validated by QIF that tumor CD44 levels assessed as continuous QIF scores were associated with longer PFS (multivariate HR=0.31, p=0.022) and overall survival (multivariate HR=0.29, p=0.038). Using DSP in an independent immunotherapy treated cohort, we validated that CD44 levels in the tumor compartment, but not in the immune compartment (panCK-/CD45+), were associated with clinical benefit (OR=1.22, p=0.018) and extended PFS under PD-1 axis inhibition using the highest tertile cutpoint (multivariate HR=0.62, p=0.03). The effect of tumor cell CD44 in predicting PFS remained significant after correcting for programmed death-ligand 1 (PD-L1) Tumor Proportion Score (TPS) in both cohorts. High tumor cell CD44 was not prognostic in the absence of immunotherapy. Using DSP data, intratumoral regions with elevated tumor cell CD44 expression showed prominent (fold change>1.5, adjusted p<0.05) upregulation of PD-L1, TIM-3, ICOS, and CD40 in two independent cohorts. Conclusions This work highlights CD44 as a novel indicative biomarker of sensitivity to PD-1 axis blockade that might help to improve immunotherapy strategies for NSCLC.
  • Autores: Valencia Leoz, Karmele (Autor de correspondencia); Sainz, C.; Bértolo Martín de Rosales, Cristina María; et al.
    Revista: DISEASE MODELS & MECHANISMS
    ISSN: 1754-8411 Vol.15 N° 1 2022 págs. dmm049137
    Resumen
    There is a paucity of adequate mouse models and cell lines available to study lung squamous cell carcinoma (LUSC). We have generated and characterized two models of phenotypically different transplantable LUSC cell lines, i.e. UN-SCC679 and UN-SCC680, derived from A/J mice that had been chemically induced with N-nitroso-tris-chloroethylurea (NTCU). Furthermore, we genetically characterized and compared both LUSC cell lines by performing whole-exome and RNA sequencing. These experiments revealed similar genetic and transcriptomic patterns that may correspond to the classic LUSC human subtype. In addition, we compared the immune landscape generated by both tumor cells lines in vivo and assessed their response to immune checkpoint inhibition. The differences between the two cell lines are a good model for the remarkable heterogeneity of human squamous cell carcinoma. Study of the metastatic potential of these models revealed that both cell lines represent the organotropism of LUSC in humans, i.e. affinity to the brain, bones, liver and adrenal glands. In summary, we have generated valuable cell line tools for LUSC research, which recapitulates the complexity of the human disease.
  • Autores: Cuttano, R.; Colangelo, T.; Guarize, J.; et al.
    Revista: JOURNAL OF HEMATOLOGY AND ONCOLOGY
    ISSN: 1756-8722 Vol.15 N° 1 2022 págs. 178
    Resumen
    Locally advanced non-small cell lung cancer (NSCLC) is frequent at diagnosis and requires multimodal treatment approaches. Neoadjuvant chemotherapy (NACT) followed by surgery is the treatment of choice for operable locally advanced NSCLC (Stage IIIA). However, the majority of patients are NACT-resistant and show persistent lymph nodal metastases (LNmets) and an adverse outcome. Therefore, the identification of mechanisms and biomarkers of NACT resistance is paramount for ameliorating the prognosis of patients with Stage IIIA NSCLC. Here, we investigated the miRNome and transcriptome of chemo-naive LNmets collected from patients with Stage IIIA NSCLC (N = 64). We found that a microRNA signature accurately predicts NACT response. Mechanistically, we discovered a miR-455-5p/PD-L1 regulatory axis which drives chemotherapy resistance, hallmarks metastases with active IFN-gamma response pathway (an inducer of PD-L1 expression), and impacts T cells viability and relative abundances in tumor microenvironment (TME). Our data provide new biomarkers to predict NACT response and add molecular insights relevant for improving the management of patients with locally advanced NSCLC.
  • Autores: Valencia Leoz, Karmele (Autor de correspondencia); Echepare, M.; Teijeira Sánchez, Álvaro; et al.
    Revista: JOURNAL OF EXPERIMENTAL MEDICINE
    ISSN: 0022-1007 Vol.219 N° 12 2022 págs. e20220726
    Resumen
    Lung cancer remains the leading cause of cancer-related death worldwide. We identify DSTYK, a dual serine/threonine and tyrosine non-receptor protein kinase, as a novel actionable target altered in non-small cell lung cancer (NSCLC). We also show DSTYK's association with a lower overall survival (OS) and poorer progression-free survival (PFS) in multiple patient cohorts. Abrogation of DSTYK in lung cancer experimental systems prevents mTOR-dependent cytoprotective autophagy, impairs lysosomal biogenesis and maturation, and induces accumulation of autophagosomes. Moreover, DSTYK inhibition severely affects mitochondrial fitness. We demonstrate in vivo that inhibition of DSTYK sensitizes lung cancer cells to TNF-alpha-mediated CD8+-killing and immune-resistant lung tumors to anti-PD-1 treatment. Finally, in a series of lung cancer patients, DSTYK copy number gain predicts lack of response to the immunotherapy. In summary, we have uncovered DSTYK as new therapeutic target in lung cancer. Prioritization of this novel target for drug development and clinical testing may expand the percentage of NSCLC patients benefiting from immune-based treatments.
  • Autores: Meraviglia-Crivelli, D.; Villanueva Ruiz, Helena; Zheleva, Angelina; et al.
    Revista: MOLECULAR CANCER
    ISSN: 1476-4598 Vol.21 N° 1 2022 págs. 211
    Resumen
    Background The quality and quantity of tumor neoantigens derived from tumor mutations determines the fate of the immune response in cancer. Frameshift mutations elicit better tumor neoantigens, especially when they are not targeted by nonsense-mediated mRNA decay (NMD). For tumor progression, malignant cells need to counteract the immune response including the silencing of immunodominant neoantigens (antigen immunoediting) and promoting an immunosuppressive tumor microenvironment. Although NMD inhibition has been reported to induce tumor immunity and increase the expression of cryptic neoantigens, the possibility that NMD activity could be modulated by immune forces operating in the tumor microenvironment as a new immunoediting mechanism has not been addressed. Methods We study the effect of SMG1 expression (main kinase that initiates NMD) in the survival and the nature of the tumor immune infiltration using TCGA RNAseq and scRNAseq datasets of breast, lung and pancreatic cancer. Different murine tumor models were used to corroborate the antitumor immune dependencies of NMD. We evaluate whether changes of SMG1 expression in malignant cells impact the immune response elicited by cancer immunotherapy. To determine how NMD fluctuates in malignant cells we generated a luciferase reporter system to track NMD activity in vivo under different immune conditions. Cytokine screening, in silico studies and functional assays were conducted to determine the regulation of SMG1 via IL-6/STAT3 signaling. Results IL-6/STAT3 signaling induces SMG1, which limits the expression of potent frameshift neoantigens that are under NMD control compromising the outcome of the immune response. Conclusion We revealed a new neoantigen immunoediting mechanism regulated by immune forces (IL-6/STAT3 signaling) responsible for silencing otherwise potent frameshift mutation-derived neoantigens.
  • Autores: Fernández Ros, Nerea (Autor de correspondencia); Alegre Garrido, Félix; Rodríguez Rodríguez, Javier; et al.
    Revista: JOURNAL OF CLINICAL MEDICINE
    ISSN: 2077-0383 Vol.11 N° 12 2022 págs. 3472
    Resumen
    Background: To analyze the long-term outcomes for advanced cancer patients admitted to an intermediate care unit (ImCU), an analysis of a do not resuscitate orders (DNR) subgroup was made. Methods: A retrospective observational study was conducted from 2006 to January 2019 in a single academic medical center of cancer patients with stage IV disease who suffered acute severe complications. The Simplified Acute Physiology Score 3 (SAPS 3) was used as a prognostic and severity score. In-hospital mortality, 30-day mortality and survival after hospital discharge were calculated. Results: Two hundred and forty patients with stage IV cancer who attended at an ImCU were included. In total, 47.5% of the cohort had DNR orders. The two most frequent reasons for admission were sepsis (32.1%) and acute respiratory failure (excluding sepsis) (38.7%). Mortality in the ImCU was 10.8%. The mean predicted in-hospital mortality according to SAPS 3 was 51.9%. The observed in-hospital mortality was 37.5% (standard mortality ratio of 0.72). Patients discharged from hospital had a median survival of 81 (30.75-391.25) days (patients with DNR orders 46 days (19.5-92.25), patients without DNR orders 162 days (39.5-632)). The observed mortality was higher in patients with DNR orders: 52.6% vs. 23.8%, p 0 < 0.001. By multivariate logistic regression, a worse ECOG performance status (3-4 vs. 0-2), a higher SAPS 3 Score and DNR orders were associated with a higher in-hospital mortality. By multivariate analysis, non-invasive mechanical ventilation, higher bilirubin levels and DNR orders were significantly associated with 30-day mortality. Conclusion: For patients with advanced cancer disease, even those with DNR orders, who suffer from acute complications or require continuous monitoring, an ImCU-centered multidisciplinary management shows encouraging results in terms of observed-to-expected mortality ratios.
  • Autores: Senent, Y.; Tavira Iglesias, Beatriz; Pio Osés, Rubén (Autor de correspondencia); et al.
    Revista: CANCER LETTERS
    ISSN: 0304-3835 Vol.549 2022 págs. 215900
    Resumen
    Tumor progression relies on the interaction between tumor cells and their surrounding tumor microenvironment (TME), which also influences therapeutic responses. The complement system, an essential part of innate im-munity, has been traditionally considered an effector arm against tumors. However, established tumors co-opt complement-mediated immune responses in the TME to support chronic inflammation, activate cancer-related signaling pathways and hamper antitumor immune responses. In this context, myeloid-derived suppressor cells (MDSCs), a heterogeneous population of myeloid progenitors with immunosuppressive functions, are recognized as major mediators of tumor-associated complement activities. This review focuses on the impact of complement activation within the TME, with a special emphasis on MDSC functions and the involvement of the C5a/C5aR1 axis. We also discuss the translation of these findings into therapeutic advances based on comple-ment inhibition.
  • Autores: Manosas, S.; Sanz, A.; Ederra Ochoa, Cristina; et al.
    Revista: MATHEMATICS
    ISSN: 2227-7390 Vol.10 N° 23 2022 págs. 4593
    Resumen
    The blood-brain barrier is a unique physiological structure acting as a filter for every molecule reaching the brain through the blood. For this reason, an effective pharmacologic treatment supplied to a patient by systemic circulation should first be capable of crossing the barrier. Standard cell cultures (or those based on microfluidic devices) and animal models have been used to study the human blood-brain barrier. Unfortunately, these tools have not yet reached a state of maturity because of the complexity of this physiological process aggravated by a high heterogeneity that is not easily recapitulated experimentally. In fact, the extensive research that has been performed and the preclinical trials carried out provided sometimes contradictory results, and the functionality of the barrier function is still not fully understood. In this study, we have combined tissue clarification, advanced microscopy and image analysis to develop a one-dimensional computational model of the microvasculature hemodynamics inside the mouse brain. This model can provide information about the flow regime, the pressure field and the wall shear stress among other fluid dynamics variables inside the barrier. Although it is a simplified model of the cerebral microvasculature, it allows a first insight on into the blood-brain barrier hemodynamics and offers several additional possibilities to systematically study the barrier microcirculatory processes.
  • Autores: Ortiz Espinosa, Sergio; Morales Urteaga, Xabier; Senent, Y.; et al.
    Revista: CANCER LETTERS
    ISSN: 0304-3835 Vol.529 2022 págs. 70 - 84
    Resumen
    Myeloid-derived suppressor cells (MDSCs) play a major role in cancer progression. In this study, we investigated the mechanisms by which complement C5a increases the capacity of polymorphonuclear MDSCs (PMN-MDSCs) to promote tumor growth and metastatic spread. Stimulation of PMN-MDSCs with C5a favored the invasion of cancer cells via a process dependent on the formation of neutrophil extracellular traps (NETs). NETosis was dependent on the production of high mobility group box 1 (HMGB1) by cancer cells. Moreover, C5a induced the surface expression of the HMGB1 receptors TLR4 and RAGE in PMN-MDSCs. In a mouse lung metastasis model, inhibition of C5a, C5a receptor-1 (C5aR1) or NETosis reduced the number of circulating-tumor cells (CTCs) and the metastatic burden. In support of the translational relevance of these findings, C5a was able to stimulate migration and NETosis in PMN-MDSCs obtained from lung cancer patients. Furthermore, myeloperoxidase (MPO)-DNA complexes, as markers of NETosis, were elevated in lung cancer patients and significantly correlated with C5a levels. In conclusion, C5a induces the formation of NETs from PMN-MDSCs in the presence of cancer cells, which may facilitate cancer cell dissemination and metastasis.
  • Autores: Meraviglia-Crivelli, D.; Ruiz-Villanueva, H.; Puravankara-Menon, A.; et al.
    Revista: MOLECULAR THERAPY - NUCLEIC ACIDS
    ISSN: 2162-2531 Vol.29 2022 págs. 413 - 425
    Resumen
    Immune-checkpoint blockade (ICB) therapy has changed the clinical outcome of many types of aggressive tumors, but there still remain many cancer patients that do not respond to these treatments. There is an unmet need to develop a feasible clinical therapeutic platform to increase the rate of response to ICB. Here we use a previously described clinically tested aptamer (AS1411) conjugated with SMG1 RNAi (AS1411-SMG1 aptamer-linked siRNA chimeras [AsiCs]) to inhibit the nonsense-mediated RNA decay pathway inducing tumor inflammation and improving response to ICB. The aptamer AS1411 shows binding to numerous mouse and human tumor cell lines tested. AS1411 induces tumor cytotoxicity in long incubation times, which allows for the use of the aptamer as a carrier to target the RNAi inhibition to the tumor. The AS1411-SMG1 AsiCs induce a strong antitumor response in local and systemic treatment in different types of tumors. Finally, AS1411-SMG1 AsiCs are well tolerated with no detected side effects.
  • Autores: Rodríguez Pena, Alejandro; Armendáriz, E.; Oyarbide, A.; et al.
    Revista: BIOENGINEERING & TRANSLATIONAL MEDICINE
    ISSN: 2380-6761 Vol.7 N° 3 2022 págs. e10331
    Resumen
    The analysis of circulating tumor cells (CTCs) in blood is a powerful noninvasive alternative to conventional tumor biopsy. Inertial-based separation is a promising high-throughput, marker-free sorting strategy for the enrichment and isolation of CTCs. Here, we present and validate a double spiral microfluidic device that efficiently isolates CTCs with a fine-tunable cut-off value of 9 mu m and a separation range of 2 mu m. We designed the device based on computer simulations that introduce a novel, customized inertial force term, and provide practical fabrication guidelines. We validated the device using calibration beads, which allowed us to refine the simulations and redesign the device. Then we validated the redesigned device using blood samples and a murine model of metastatic breast cancer. Finally, as a proof of principle, we tested the device using peripheral blood from a patient with hepatocellular carcinoma, isolating more than 17 CTCs/ml, with purity/removal values of 96.03% and 99.99% of white blood cell and red blood cells, respectively. These results confirm highly efficient CTC isolation with a stringent cut-off value and better separation results than the state of the art.
  • Autores: Felberg-Mietka, A.; Urban, A.; Kuzniewska, A.; et al.
    Revista: MOLECULAR IMMUNOLOGY
    ISSN: 0161-5890 Vol.141 2022 págs. 129 - 129
  • Autores: Leon Valencia, Sergio; Serrano Tejero, Diego; Redín Cabodevilla, María Esther; et al.
    Revista: CANCER RESEARCH
    ISSN: 0008-5472 Vol.82 N° 12 2022
  • Autores: Moutafi, M.; Molero, M.; Martínez-Morilla, S.; et al.
    Revista: CANCER RESEARCH
    ISSN: 0008-5472 Vol.82 N° 12 S 2022 págs. 2028
    Resumen
    Background: Most patients with advanced non-small-cell lung cancer (NSCLC) fail to derive significant benefit from programmed cell death protein-1 (PD-1) axis blockade, and new biomarkers of response are needed. In this study, we aimed to discover and validate spatially resolved protein markers associated with sensitivity to PD-1 axis inhibition in NSCLC. Methods: We initially assessed a discovery cohort of 56 patients with NSCLC treated with PD-1 axis inhibitors at Yale Cancer Center. Using the GeoMx Digital Spatial Profiling (DSP) system, 71 proteins were measured in spatial context on each spot in a tissue microarray. We used the AQUA method of quantitative immunofluorescence (QIF) to orthogonally validate candidate biomarkers. For external independent validation, we assessed whole tissue sections derived from 128 patients with NSCLC treated with single-agent PD-1 axis inhibitors at the 12 de Octubre Hospital (Madrid) using DSP. We further analyzed two immunotherapy untreated cohorts to address prognostic significance (n=252 from Yale Cancer Center; n=124 from University Clinic of Navarra) using QIF and DSP, respectively. Results: Using continuous log-scaled data, we identified CD44 expression in the tumor compartment (pan-cytokeratin (CK)+) as a novel predictor of prolonged progression-free survival (PFS) (multivariate HR=0.68, p=0.043) in the discovery set. We validated by QIF that tumor CD44 levels assessed as continuous QIF scores were associated with longer PFS (multivariate HR=0.31, p=0.022) and overall survival (multivariate HR=0.29, p=0.038). Using DSP in an independent immunotherapy treated cohort, we validated that CD44 levels in the tumor compartment, but not in the immune compartment (panCK-/CD45+), were associated with clinical benefit (OR=1.22, p=0.018) and extended PFS under PD-1 axis inhibition using the highest tertile cutpoint (multivariate HR=0.62, p=0.03). The effect of tumor cell CD44 in predicting PFS remained significant after correcting for programmed death-ligand 1 (PD-L1) Tumor Proportion Score (TPS) in both cohorts. High tumor cell CD44 was not prognostic in the absence of immunotherapy. Using DSP data, intratumoral regions with elevated tumor cell CD44 expression showed prominent (fold change>1.5, adjusted p<0.05) upregulation of PD-L1, TIM-3, ICOS, and CD40 in two independent cohorts. Conclusions: This work highlights CD44 as a novel indicative biomarker of sensitivity to PD-1 axis blockade that might help to improve immunotherapy strategies for NSCLC.
  • Autores: González-Larreategui, I.; Vera Álvarez, Laura; Giuntini, F.; et al.
    Revista: EUROPEAN JOURNAL OF CANCER
    ISSN: 0959-8049 Vol.174 N° SUPPL 1 2022 págs. S47 - S47
  • Autores: Redín Cabodevilla, María Esther; Garrido-Martin, E. M.; Valencia Leoz, Karmele; et al.
    Revista: CANCER RESEARCH
    ISSN: 0008-5472 Vol.82 N° 12 2022
  • Autores: Montuenga Badía, Luis; Aguirre-Ruiz, P.; Ariceta Ganuza, Beñat; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN: 0923-7534 Vol.33 N° Supl. 2 2022 págs. S110
  • Autores: Valencia Leoz, Karmele; Sainz, C.; Redrado Jordán, Miriam; et al.
    Revista: JOURNAL OF THORACIC ONCOLOGY
    ISSN: 1556-0864 Vol.17 N° 9 2022 págs. S559 - S559
  • Autores: Valencia Leoz, Karmele (Autor de correspondencia); Montuenga Badía, Luis (Autor de correspondencia)
    Revista: CANCERS
    ISSN: 2072-6694 Vol.13 N° 9 2021 págs. 2147
    Resumen
    Among the different components that can be analyzed in liquid biopsy, the utility of exosomes is particularly promising because of their presence in all biological fluids and their potential for multicomponent analyses. Exosomes are extracellular vesicles with an average size of similar to 100 nm in diameter with an endosomal origin. All eukaryotic cells release exosomes as part of their active physiology. In an oncologic patient, up to 10% of all the circulating exosomes are estimated to be tumor-derived exosomes. Exosome content mirrors the features of its cell of origin in terms of DNA, RNA, lipids, metabolites, and cytosolic/cell-surface proteins. Due to their multifactorial content, exosomes constitute a unique tool to capture the complexity and enormous heterogeneity of cancer in a longitudinal manner. Due to molecular features such as high nucleic acid concentrations and elevated coverage of genomic driver gene sequences, exosomes will probably become the "gold standard" liquid biopsy analyte in the near future.
  • Autores: Morales Urteaga, Xabier; Cortes Domínguez, Iván; Ortiz de Solórzano Aurusa, Carlos (Autor de correspondencia)
    Revista: GELS
    ISSN: 2310-2861 Vol.7 N° 1 2021 págs. 17
    Resumen
    Understanding how cancer cells migrate, and how this migration is affected by the mechanical and chemical composition of the extracellular matrix (ECM) is critical to investigate and possibly interfere with the metastatic process, which is responsible for most cancer-related deaths. In this article we review the state of the art about the use of hydrogel-based three-dimensional (3D) scaffolds as artificial platforms to model the mechanobiology of cancer cell migration. We start by briefly reviewing the concept and composition of the extracellular matrix (ECM) and the materials commonly used to recreate the cancerous ECM. Then we summarize the most relevant knowledge about the mechanobiology of cancer cell migration that has been obtained using 3D hydrogel scaffolds, and relate those discoveries to what has been observed in the clinical management of solid tumors. Finally, we review some recent methodological developments, specifically the use of novel bioprinting techniques and microfluidics to create realistic hydrogel-based models of the cancer ECM, and some of their applications in the context of the study of cancer cell migration.
  • Autores: Senent, Y.; Ajona Martínez-Polo, Daniel (Autor de correspondencia); González Martín, Antonio; et al.
    Revista: CANCERS
    ISSN: 2072-6694 Vol.13 N° 15 2021 págs. 3806
    Resumen
    Simple Summary Ovarian cancer is one of the leading causes of death among women and the most lethal cause of death from gynecological malignancy in developed countries. The immune system plays an essential role in ovarian cancer progression, and its modulation may be used as an effective therapeutic tool. In this review, we examine the relevance of the cellular and humoral components of the adaptive and innate immune responses in ovarian cancer, focusing on the role of an essential component of innate immunity, the complement system. Elements of this system show tumor-promoting activities that impede the efficacy of developing treatment strategies. We discuss evidence that suggests a role of complement components in the progression of ovarian cancer and provide a rationale for evaluating the inhibition of complement components in combination with immunotherapies aimed to reactivate antitumor T-cell responses. Ovarian cancer is one of the most lethal gynecological cancers. Current therapeutic strategies allow temporary control of the disease, but most patients develop resistance to treatment. Moreover, although successful in a range of solid tumors, immunotherapy has yielded only modest results in ovarian cancer. Emerging evidence underscores the relevance of the components of innate and adaptive immunity in ovarian cancer progression and response to treatment. Particularly, over the last decade, the complement system, a pillar of innate immunity, has emerged as a major regulator of the tumor microenvironment in cancer immunity. Tumor-associated complement activation may support chronic inflammation, promote an immunosuppressive microenvironment, induce angiogenesis, and activate cancer-related signaling pathways. Recent insights suggest an important role of complement effectors, such as C1q or anaphylatoxins C3a and C5a, and their receptors C3aR and C5aR1 in ovarian cancer progression. Nevertheless, the implication of these factors in different clinical contexts is still poorly understood. Detailed knowledge of the interplay between ovarian cancer cells and complement is required to develop new immunotherapy combinations and biomarkers. In this context, we discuss the possibility of targeting complement to overcome some of the hurdles encountered in the treatment of ovarian cancer.
  • Autores: Jablonska, Paola Anna (Autor de correspondencia); Bosch Barrera, Joaquim; Serrano Tejero, Diego; et al.
    Revista: CANCERS
    ISSN: 2072-6694 Vol.13 N° 9 2021 págs. 2141
    Resumen
    Simple Summary Lung cancer is the most common primary malignancy that tends to metastasize to the brain. Owing to improved survival of lung cancer patients, the prevalence of brain metastases is a matter of growing concern. Brain radiotherapy remains the mainstay in the management of metastatic CNS disease. However, new targeted therapies such as the tyrosine kinase or immune checkpoint inhibitors have demonstrated intracranial activity and promising tumor response rates. Here, we review the current and emerging therapeutical strategies for brain metastases from non-small cell lung cancer, both brain-directed and systemic, as well as the uncertainties that may arise from their combination. Approximately 20% patients with non-small cell lung cancer (NSCLC) present with CNS spread at the time of diagnosis and 25-50% are found to have brain metastases (BMs) during the course of the disease. The improvement in the diagnostic tools and screening, as well as the use of new systemic therapies have contributed to a more precise diagnosis and prolonged survival of lung cancer patients with more time for BMs development. In the past, most of the systemic therapies failed intracranially because of the inability to effectively cross the blood brain barrier. Some of the new targeted therapies, especially the group of tyrosine kinase inhibitors (TKIs) have shown durable CNS response. However, the use of ionizing radiation remains vital in the management of metastatic brain disease. Although a decrease in CNS-related deaths has been achieved over the past decade, many challenges arise from the need of multiple and repeated brain radiation treatments, which carry along not insignificant risks and toxicity. The combination of stereotactic radiotherapy and systemic treatments in terms of effectiveness and adverse effects, such as radionecrosis, remains a subject of ongoing investigation. This review discusses the challenges of the use of radiation therapy in NSCLC BMs in view of different systemic treatments such as chemotherapy, TKIs and immunotherapy. It also outlines the future perspectives and strategies for personalized BMs management.
  • Autores: Montuenga Badía, Luis (Autor de correspondencia)
    Revista: MAGAZINE OF EUROPEAN MEDICAL ONCOLOGY
    ISSN: 1865-5041 Vol.14 N° Suppl. 3 2021 págs. S62 - S63
  • Autores: Morales Urteaga, Xabier; Peláez, R.; Garasa, S.; et al.
    Revista: BIOMOLECULES
    ISSN: 2218-273X Vol.11 N° 10 2021 págs. 1533
    Resumen
    Collapsin response mediator protein 2 (CRMP2) is an adaptor protein that adds tubulin dimers to the growing tip of a microtubule. First described in neurons, it is now considered a ubiquitous protein that intervenes in processes such as cytoskeletal remodeling, synaptic connection and trafficking of voltage channels. Mounting evidence supports that CRMP2 plays an essential role in neuropathology and, more recently, in cancer. We have previously described a positive correlation between nuclear phosphorylation of CRMP2 and poor prognosis in lung adenocarcinoma patients. In this work, we studied whether this cytoskeleton molding protein is involved in cancer cell migration. To this aim, we evaluated CRMP2 phosphorylation and localization in the extending lamella of lung adenocarcinoma migrating cells using in vitro assays and in vivo confocal microscopy. We demonstrated that constitutive phosphorylation of CRMP2 impaired lamella formation, cell adhesion and oriented migration. In search of a mechanistic explanation of this phenomenon, we discovered that CRMP2 Ser522 phospho-mimetic mutants display unstable tubulin polymers, unable to bind EB1 plus-Tip protein and the cortical actin adaptor IQGAP1. In addition, integrin recycling is defective and invasive structures are less evident in these mutants. Significantly, mouse xenograft tumors of NSCLC expressing CRMP2 phosphorylation mimetic mutants grew significantly less than wild-type tumors.
  • Autores: Esteban, E.; Expósito Rincón, Francisco; Crespo, G.; et al.
    Revista: CANCERS
    ISSN: 2072-6694 Vol.13 N° 11 2021 págs. 2849
    Resumen
    We have studied blood levels of cytokines/chemokines in patients with metastatic renal cell carcinoma treated with sunitinib or pazopanib, with the goal of identifying biomarkers that can predict efficacy and survival. We have found that high levels of CXCL10, CXCL11, HGF and IL-6 before treatment associate with poor prognosis in these patients. Moreover, these factors are correlated in patients with renal carcinoma, suggesting a coordinated expression and secretion. We have developed a prognostic signature including these factors that predicts very accurately prognosis. Our results may help defining better the group of renal cell carcinoma patients who may benefit from sunitinib/pazopanib.
  • Autores: Rodríguez-Arce, I.; Morales Urteaga, Xabier; Ariz Galilea, Mikel; et al.
    Revista: VIRULENCE
    ISSN: 2150-5594 Vol.12 N° 1 2021 págs. 1672 - 1688
    Resumen
    Chronic obstructive pulmonary disease (COPD) patients undergo infectious exacerbations whose frequency identifies a clinically meaningful phenotype. Mouse models have been mostly used to separately study both COPD and the infectious processes, but a reliable model of the COPD frequent exacerbator phenotype is still lacking. Accordingly, we first established a model of single bacterial exacerbation by nontypeable Haemophilus influenzae (NTHi) infection on mice with emphysema-like lesions. We characterized this single exacerbation model combining both noninvasive in vivo imaging and ex vivo techniques, obtaining longitudinal information about bacterial load and the extent of the developing lesions and host responses. Bacterial load disappeared 48 hours post-infection (hpi). However, lung recovery, measured using tests of pulmonary function and the disappearance of lung inflammation as revealed by micro-computed X-ray tomography, was delayed until 3 weeks post-infection (wpi). Then, to emulate the frequent exacerbator phenotype, we performed two recurrent episodes of NTHi infection on the emphysematous murine lung. Consistent with the amplified infectious insult, bacterial load reduction was now observed 96 hpi, and lung function recovery and disappearance of lesions on anatomical lung images did not happen until 12 wpi. Finally, as a proof of principle of the use of the model, we showed that azithromycin successfully cleared the recurrent infection, confirming this macrolide utility to ameliorate infectious exacerbation. In conclusion, we present a mouse model of recurrent bacterial infection of the emphysematous lung, aimed to facilitate investigating the COPD frequent exacerbator phenotype by providing complementary, dynamic information of both infectious and inflammatory processes.
  • Autores: Yuan, G.; Flores, N. M.; Hausmann, S.; et al.
    Revista: NATURE
    ISSN: 0028-0836 Vol.590 N° 7846 2021 págs. 504 - 508
    Resumen
    Amplification of chromosomal region 8p11-12 is a common genetic alteration that has been implicated in the aetiology of lung squamous cell carcinoma (LUSC)(1-3). The FGFR1 gene is the main candidate driver of tumorigenesis within this region(4). However, clinical trials evaluating FGFR1 inhibition as a targeted therapy have been unsuccessful(5). Here we identify the histone H3 lysine 36 (H3K36) methyltransferase NSD3, the gene for which is located in the 8p11-12 amplicon, as a key regulator of LUSC tumorigenesis. In contrast to other 8p11-12 candidate LUSC drivers, increased expression of NSD3 correlated strongly with its gene amplification. Ablation of NSD3, but not of FGFR1, attenuated tumour growth and extended survival in a mouse model of LUSC. We identify an LUSC-associated variant NSD3(T1232A) that shows increased catalytic activity for dimethylation of H3K36 (H3K36me2) in vitro and in vivo. Structural dynamic analyses revealed that the T1232A substitution elicited localized mobility changes throughout the catalytic domain of NSD3 to relieve auto-inhibition and to increase accessibility of the H3 substrate. Expression of NSD3(T1232A) in vivo accelerated tumorigenesis and decreased overall survival in mouse models of LUSC. Pathological generation of H3K36me2 by NSD3(T1232A) reprograms the chromatin landscape to promote oncogenic gene expression signatures. Furthermore, NSD3, in a manner dependent on its catalytic activity, promoted transformation in human tracheobronchial cells and growth of xenografted human LUSC cell lines with amplification of 8p11-12. Depletion of NSD3 in patient-derived xenografts from primary LUSCs containing NSD3 amplification or the NSD3(T1232A)-encoding variant attenuated neoplastic growth in mice. Finally, NSD3-regulated LUSC-derived xenografts were hypersensitive to bromodomain inhibition. Thus, our work identifies NSD3 as a principal 8p11-12 amplicon-associated oncogenic driver in LUSC, and suggests that NSD3-dependency renders LUSC therapeutically vulnerable to bromodomain inhibition.
  • Autores: Sánchez-Canteli, M.; Juesas, L.; Redín Cabodevilla, María Esther; et al.
    Revista: CANCERS
    ISSN: 2072-6694 Vol.13 N° 9 2021 págs. 2079
    Resumen
    Our goal was to assess the correlation of immune parameters with the response to induction chemotherapy (ICT) in head and neck squamous cell carcinoma (HNSCC) patients. Pretreatment biopsies from 64 patients with HNSCC that received ICT were assessed for PD-L1 protein expression and density of CD8+ and FOXP3+ tumor infiltrating lymphocytes (TIL). In addition, the neutrophil-to-lymphocyte ratio (NLR) was calculated from pretreatment whole blood counts. In total, 55% of cases exhibited PD-L1 combined proportion score (CPS) positivity (¿1% stained cells). PD-L1 CPS positivity correlated with a high density of both CD8+ (p = 0.01) and FOXP3+ (p < 0.001) TILs. There was no correlation between PD-L1 expression or TIL density and NLR values. In univariate analyses, the absence of PD-L1 CPS expression (p = 0.042) and a high NLR (p = 0.034) were significantly correlated with response to ICT. Neither CD8+ TIL (p = 0.99) nor FOXP3+ TIL densities (p = 0.71) were associated with response to ICT. In multivariate analysis, only a high NLR was associated with response to ICT (HR = 4.06, 95% CI = 1.06¿15.5, p = 0.04). In addition, a high NLR was also independently associated with lower disease-specific (p = 0.03) and overall survival rates (p = 0.04), particularly in the subset of patients who received definitive surgical treatment. These results suggest that NLR could emerge as a predictive biomarker of response to ICT.
  • Autores: Anfray, C.; Mainini, F.; Digifico, E.; et al.
    Revista: JOURNAL FOR IMMUNOTHERAPY OF CANCER
    ISSN: 2051-1426 Vol.9 N° 9 2021 págs. e002408
    Resumen
    Background Tumor-associated macrophages (TAMs) play a key immunosuppressive role that limits the ability of the immune system to fight cancer and hinder the antitumoral efficacy of most treatments currently applied in the clinic. Previous studies have evaluated the antitumoral immune response triggered by (TLR) agonists, such as poly(I:C), imiquimod (R837) or resiquimod (R848) as monotherapies; however, their combination for the treatment of cancer has not been explored. This study investigates the antitumoral efficacy and the macrophage reprogramming triggered by poly(I:C) combined with R848 or with R837, versus single treatments. Methods TLR agonist treatments were evaluated in vitro for toxicity and immunostimulatory activity by Alamar Blue, ELISA and flow cytometry using primary human and murine M-CSF-differentiated macrophages. Cytotoxic activity of TLR-treated macrophages toward cancer cells was evaluated with an in vitro functional assay by flow cytometry. For in vivo experiments, the CMT167 lung cancer model and the MN/MCA1 fibrosarcoma model metastasizing to lungs were used; tumor-infiltrating leukocytes were evaluated by flow cytometry, RT-qPCR, multispectral immunophenotyping, quantitative proteomic experiments, and protein-protein interaction analysis. Results Results demonstrated the higher efficacy of poly(I:C) combined with R848 versus single treatments or combined with R837 to polarize macrophages toward M1-like antitumor effectors in vitro.
  • Autores: Piulats, J. M. (Autor de correspondencia); Espinosa, E.; Merino, L. D.; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN: 0732-183X Vol.39 N° 6 2021 págs. 586 - 598
    Resumen
    PURPOSE This study aimed to assess the efficacy of the combination of nivolumab (nivo) plus ipilimumab (ipi) as a first-line therapy with respect to the 12-month overall survival (OS) in patients with metastatic uveal melanoma (MUM) who are not eligible for liver resection. METHODS This was a single-arm, phase II trial led by the Spanish Multidisciplinary Melanoma Group (GEM) on nivo plus ipi for systemic treatment-naive patients of age. 18 years, with histologically confirmed MUM, Eastern Cooperative Oncology Group-PS 0/1, and confirmed progressive metastatic disease (M1). Nivo (1 mg/kg once every 3 weeks) and ipi (3 mg/kg once every 3 weeks) were administered during four inductions, followed by nivo (3 mg/kg once every 2 weeks) until progressive disease, toxicity, or withdrawal. The primary end point was 12-month OS. OS, progression-free survival (PFS), and overall response rate were evaluated every 6 weeks using RECIST (v1.1). Safety was also evaluated. Logistic regression and Cox proportional hazard models comprising relevant clinical factors were used to evaluate the potential association with response to treatment and survival. Cytokines were quantified in serum samples for their putative role in immune modulation/angiogenesis and/or earlier evidence of involvement in immunotherapy. RESULTS A total of 52 patients with a median age of 59 years (range, 26-84 years) were enrolled. Overall, 78.8%, 56%, and 32% of patients had liver M1, extra-liver M1, and elevated lactate dehydrogenase. Stable disease was the most common outcome (51.9%). The primary end point was 12-month OS, which was 51.9% (95% CI, 38.3 to 65.5). The median OS and PFS were 12.7 months and 3.0 months, respectively. PFS was influenced by higher LDH values. CONCLUSIONS Nivo plus ipi in the first-line setting for MUM showed a modest improvement in OS over historical benchmarks of chemotherapy, with a manageable toxicity profile. (C) 2021 by American Society of Clinical Oncology
  • Autores: Bellmunt, J. (Autor de correspondencia); Esteban, E.; Garcia del Muro, X.; et al.
    Revista: EUROPEAN UROLOGY
    ISSN: 0302-2838 Vol.4 N° 3 2021 págs. 502 - 505
    Resumen
    Pazopanib is an oral angiogenesis tyrosine kinase inhibitor (TKI) recommended in metastatic renal cell carcinoma (mRCC) for treatment-naive patients or those experiencing cytokine failure. We conducted a phase 2, open-label, single-arm study in ten Spanish centres among mRCC patients whose disease progressed on first-line TKI. Patients received pazopanib until disease progression, death, or unacceptable toxicity. Twenty-seven patients were included (median age 62 yr, 51.9% male). The objective overall response rate was 14.8% (95% confidence interval [CI] 1.4-28.2%). Median progression-free survival was 6.7 mo (95% CI 3.7-11.2) and median overall survival was 20.6 mo (95% CI 12.6-27.4). Lower circulating levels of IL-10 (p = 0.002) were observed in responding patients at 8 wk after treatment. The median pazopanib treatment duration was 6.0 mo (range 1.0-47.0). Most patients (48.1%) had mild or moderate adverse events (AEs), while 44.4% had severe AEs. Pazopanib was clinically active and well tolerated as a second-line treatment in mRCC patients after TKI failure, and circulating IL-10 levels could predict response. Patient summary: Pazopanib could be used as a second-line therapy for the treatment of metastatic renal cell carcinoma after failure of tyrosine kinase inhibitor (TKI) therapy when drugs such as nivolumab and cabozantinib are not available.
  • Autores: Palanca-Ballester, C.; Rodríguez Casanova, A.; Torres, S.; et al.
    Revista: CANCERS
    ISSN: 2072-6694 Vol.13 N° 12 2021 págs. 3016
    Resumen
    Simple Summary Apart from genetic changes, cancer is characterized by epigenetic alterations, which indicate modifications in the DNA (such as DNA methylation) and histones (such as methylation and acetylation), as well as gene expression regulation by non-coding (nc)RNAs. These changes can be used in biological fluids (liquid biopsies) for diagnosis, prognosis and prediction of cancer drug response. Although these alterations are not widely used as biomarkers in the clinical practice yet, increasing number of commercial kits and clinical trials are expected to prove that epigenetic changes are able to offer valuable information for cancer patients. Early alterations in cancer include the deregulation of epigenetic events such as changes in DNA methylation and abnormal levels of non-coding (nc)RNAs. Although these changes can be identified in tumors, alternative sources of samples may offer advantages over tissue biopsies. Because tumors shed DNA, RNA, and proteins, biological fluids containing these molecules can accurately reflect alterations found in cancer cells, not only coming from the primary tumor, but also from metastasis and from the tumor microenvironment (TME). Depending on the type of cancer, biological fluids encompass blood, urine, cerebrospinal fluid, and saliva, among others. Such samples are named with the general term "liquid biopsy" (LB).
  • Autores: Aguado, C.; Teixido, C.; Roman, R.; et al.
    Revista: MOLECULAR ONCOLOGY
    ISSN: 1574-7891 Vol.15 N° 2 2021 págs. 350 - 363
    Resumen
    MET inhibitors have shown activity in non-small-cell lung cancer patients (NSCLC) with MET amplification and exon 14 skipping (MET Delta ex14). However, patient stratification is imperfect, and thus, response rates have varied widely. Here, we studied MET alterations in 474 advanced NSCLC patients by nCounter, an RNA-based technique, together with next-generation sequencing (NGS), fluorescence in situ hybridization (FISH), immunohistochemistry (IHC), and reverse transcriptase polymerase chain reaction (RT-PCR), exploring correlation with clinical benefit. Of the 474 samples analyzed, 422 (89%) yielded valid results by nCounter, which identified 13 patients (3%) with MET Delta ex14 and 15 patients (3.5%) with very-high MET mRNA expression. These two subgroups were mutually exclusive, displayed distinct phenotypes and did not generally coexist with other drivers. For MET Delta ex14, 3/8 (37.5%) samples positive by nCounter tested negative by NGS. Regarding patients with very-high MET mRNA, 92% had MET amplification by FISH and/or NGS. However, FISH failed to identify three patients (30%) with very-high MET RNA expression, among which one received MET tyrosine kinase inhibitor treatment deriving clinical benefit. Our results indicate that quantitative mRNA-based techniques can improve the selection of patients for MET-targeted therapies.
  • Autores: Horgan, D.; Ciliberto, G.; Conte, P.; et al.
    Revista: CANCERS
    ISSN: 2072-6694 Vol.13 N° 3 2021 págs. 583
    Resumen
    Simple Summary The increasing number of data supporting use of a personalized approach in cancer treatment, is changing the path of patient's management. In the same time, the availability of technologies should allow patients to receive the best test for the specific individual condition. This is theoretically true, when a specific test is designed for the specific disease condition, while it is difficult to implement in the setting of agnostic therapies. Financial sources availability related to the non homogeneous health systems working in the different countries do not allow for an immediate implementation of the technologies and test commercially available. Future perspectives for targeted oncology include tumor-agnostic drugs, which target a given mutation and could be used in treating cancers from multiple organ types. Therefore, the present paper is aimed to both underline a how much important is this new view and also to sensitize the international bodies that supervise health policies at the decision-making level, with the aim of harmonizing cancer treatment pathways in at least all European countries. Rapid and continuing advances in biomarker testing are not being matched by uptake in health systems, and this is hampering both patient care and innovation. It also risks costing health systems the opportunity to make their services more efficient and, over time, more economical. The potential that genomics has brought to biomarker testing in diagnosis, prediction and research is being realised, pre-eminently in many cancers, but also in an ever-wider range of conditions-notably BRCA1/2 testing in ovarian, breast, pancreatic and prostate cancers. Nevertheless, the implementation of genetic testing in clinical routine setting is still challenging. Development is impeded by country-related heterogeneity, data deficiencies, and lack of policy alignment on standards, approval-and the role of real-world evidence in the process-and reimbursement. The acute nature of the problem is compellingly illustrated by the particular challenges facing the development and use of tumour agnostic therapies, where the gaps in preparedness for taking advantage of this innovative approach to cancer therapy are sharply exposed. Europe should already have in place a guarantee of universal access to a minimum suite of biomarker tests and should be planning for an optimum testing scenario with a wider range of biomarker tests integrated into a more sophisticated health system articulated around personalised medicine. Improving healthcare and winning advantages for Europe's industrial competitiveness and innovation require an appropriate policy framework-starting with an update to outdated recommendations. We show herein the main issues and proposals that emerged during the previous advisory boards organised by the European Alliance for Personalized Medicine which mainly focus on possible scenarios of harmonisation of both oncogenetic testing and management of cancer patients.
  • Autores: Frigola, J.; Navarro, A.; Carbonell, C.; et al.
    Revista: MOLECULAR ONCOLOGY
    ISSN: 1574-7891 Vol.15 N° 4 2021 págs. 887 - 900
    Resumen
    Immunotherapy has transformed advanced non-small cell lung cancer (NSCLC) treatment strategies and has led to unprecedented long-lasting responses in some patients. However, the molecular determinants driving these long-term responses remain elusive. To address this issue, we performed an integrative analysis of genomic and transcriptomic features of long-term immune checkpoint inhibitors (ICIs)-associated responders. We assembled a cohort of 47 patients with NSCLC receiving ICIs that was enriched in long-term responders [>18 months of progression-free survival (PFS)]. We performed whole-exome sequencing from tumor samples, estimated the tumor mutational burden (TMB), and inferred the somatic copy number alterations (SCNAs). We also obtained gene transcription data for a subset of patients using Nanostring, which we used to assess the tumor immune infiltration status and PD-L1 expression. Our results indicate that there is an association between TMB and benefit to ICIs, which is driven by those patients with long-term response. Additionally, high SCNAs burden is associated with poor response and negatively correlates with the presence of several immune cell types (B cells, natural killers, regulatory T cells or effector CD8 T cells). Also, CD274 (PD-L1) expression is increased in patients with benefit, mainly in those with long-term response. In our cohort, combined assessment of TMB and SCNAs burden enabled identification of long-term responders (considering PFS and overall survival). Notably, the association between TMB, SCNAs burden, and PD-L1 expression with the outcomes of ICIs treatment was validated in two public datasets of ICI-treated patients with NSCLC. Thus, our data indicate that TMB is associated with long-term benefit following ICIs treatment in NSCLC and that TMB, SCNAs burden, and PD-L1 are complementary determinants of response to ICIs.
  • Autores: Bilal, F.; Arenas, E. J.; Pedersen, K.; et al.
    Revista: CANCER RESEARCH
    ISSN: 0008-5472 Vol.81 N° 14 2021 págs. 3849 - 3861
    Resumen
    Activating mutations in some isoforms of RAS or RAF are drivers of a substantial proportion of cancers. The main Raf effector, MEK1/2, can be targeted with several highly specific inhibitors. The clinical activity of these inhibitors seems to be mixed, showing efficacy against mutant BRAF-driven tumors but not KRAS-driven tumors, such as pancreatic adenocarcinomas. To improve our understanding of this context- dependent efficacy, we generated pancreatic cancer cells resistant to MEK1/2 inhibition, which were also resistant to KRAS and ERK1/2 inhibitors. Compared with parental cells, inhibitor-resistant cells showed several phenotypic changes including increased metastatic ability in vivo. The transcription factor SLUG, which is known to induce epithelial-to-mesenchymal transition, was identified as the key factor responsible for both resistance to MEK1/2 inhibition and increased metastasis. Slug, but not similar transcription factors, predicted poor prognosis of pancreatic cancer patients and induced the transition to a cellular phenotype in which cell-cycle progression becomes independent of the KRASRAF-MEK1/2-ERK1/2 pathway. SLUG was targeted using two independent strategies: (i) inhibition of the MEK5-ERK5 pathway, which is responsible for upregulation of SLUG upon MEK1/2 inhibition, and (ii) direct PROTAC-mediated degradation. Both strategies were efficacious in preclinical pancreatic cancer models, paving the path for the development of more effective therapies against pancreatic cancer. Significance: This study demonstrates that SLUG confers resistance to MEK1/2 inhibitors in pancreatic cancer by uncoupling tumor progression from KRAS-RAF-MEK1/2-ERK1/2 signaling, providing new therapeutic opportunities.
  • Autores: Ajona Martínez-Polo, Daniel; Remírez, A.; Sainz, C.; et al.
    Revista: TRANSLATIONAL RESEARCH
    ISSN: 1931-5244 Vol.233 2021 págs. 77 - 91
    Resumen
    Lung cancer screening detects early-stage cancers, but also a large number of benign nodules. Molecular markers can help in the lung cancer screening process by refining inclusion criteria or guiding the management of indeterminate pulmonary nodules. In this study, we developed a diagnostic model based on the quantification in plasma of complement-derived fragment C4c, cytokeratin fragment 21-1 (CYFRA 21-1) and C-reactive protein (CRP). The model was first validated in two independent cohorts, and showed a good diagnostic performance across a range of lung tumor types, emphasizing its high specificity and positive predictive value. We next tested its utility in two clinically relevant contexts: assessment of lung cancer risk and nodule malignancy. The scores derived from the model were associated with a significantly higher risk of having lung cancer in asymptomatic individuals enrolled in a computed tomography (CT)-screening program (OR = 1.89; 95% CI = 1.20-2.97). Our model also served to discriminate between benign and malignant pulmonary nodules (AUC: 0.86; 95% CI = 0.80-0.92) with very good specificity (92%). Moreover, the model performed better in combination with clinical factors, and may be used to reclassify patients with intermediate-risk indeterminate pulmonary nodules into patients who require a more aggressive work-up. In conclusion, we propose a new diagnostic biomarker panel that may dictate which incidental or screening-detected pulmonary nodules require a more active work-up. (Translational Research 2021; 233:77-91)
  • Autores: Vallejo Blanco, Adrián; Erice Azparren, Oihane; Entrialgo Cadierno, Rodrigo; et al.
    Revista: JOURNAL OF HEPATOLOGY
    ISSN: 1600-0641 Vol.75 N° 2 2021 págs. 363 - 376
    Resumen
    Background & aims: Cholangiocarcinoma (CCA) is a neoplasia of the biliary tract driven by genetic, epigenetic and transcriptional mechanisms. Herein, we investigated the role of the transcription factor FOSL1, as well as its downstream transcriptional effectors, in the development and progression of CCA. Methods: FOSL1 was investigated in human CCA clinical samples. Genetic inhibition of FOSL1 in human and mouse CCA cell lines was performed in in vitro and in vivo models using constitutive and inducible short-hairpin RNAs. Conditional FOSL1 ablation was done using a genetically engineered mouse (GEM) model of CCA (mutant KRAS and Trp53 knockout). Follow-up RNA and chromatin immunoprecipitation (ChIP) sequencing analyses were carried out and downstream targets were validated using genetic and pharmacological inhibition. Results: An inter-species analysis of FOSL1 in CCA was conducted. First, FOSL1 was found to be highly upregulated in human and mouse CCA, and associated with poor patient survival. Pharmacological inhibition of different signalling pathways in CCA cells converged on the regulation of FOSL1 expression. Functional experiments showed that FOSL1 is required for cell proliferation and cell cycle progression in vitro, and for tumour growth and tumour maintenance in both orthotopic and subcutaneous xenograft models. Likewise, FOSL1 genetic abrogation in a GEM model of CCA extended mouse survival by decreasing the oncogenic potential of transformed cholangiocytes. RNA and ChIP sequencing studies identified direct and indirect transcriptional effectors such as HMGCS1 and AURKA, whose genetic and pharmacological inhibition phenocopied FOSL1 loss. Conclusions: Our data illustrate the functional and clinical relevance of FOSL1 in CCA and unveil potential targets amenable to pharmacological inhibition that could enable the implementation of novel therapeutic strategies. Lay summary: Understanding the molecular mechanisms involved in cholangiocarcinoma (bile duct cancer) development and progression stands as a critical step for the development of novel therapies. Through an inter-species approach, this study provides evidence of the clinical and functional role of the transcription factor FOSL1 in cholangiocarcinoma. Moreover, we report that downstream effectors of FOSL1 are susceptible to pharmacological inhibition, thus providing new opportunities for therapeutic intervention.
  • Autores: Mesa Guzmán, MIguel Alejandro (Autor de correspondencia); González Gutiérrez, Jessica; Alcaide Ocaña, Ana Belén; et al.
    Revista: ARCHIVOS DE BRONCONEUMOLOGIA
    ISSN: 0300-2896 Vol.57 N° 2 2021 págs. 101 - 106
    Resumen
    (2021);57(2):101?106
  • Autores: Senent, Y.; Inoges Sancho, Susana Inmaculada; López Díaz de Cerio, Ascensión; et al.
    Revista: FRONTIERS IN IMMUNOLOGY
    ISSN: 1664-3224 Vol.12 2021 págs. 767376
    Resumen
    Evidence supports a role of complement anaphylatoxin C5a in the pathophysiology of COVID-19. However, information about the evolution and impact of C5a levels after hospital discharge is lacking. We analyzed the association between circulating C5a levels and the clinical evolution of hospitalized patients infected with SARS-CoV-2. Serum C5a levels were determined in 32 hospitalized and 17 non-hospitalized patients from Clinica Universidad de Navarra. One hundred and eighty eight serial samples were collected during the hospitalization stay and up to three months during the follow-up. Median C5a levels were 27.71 ng/ml (25th to 75th percentile: 19.35-34.96) for samples collected during hospitalization, versus 16.76 ng/ml (12.90-25.08) for samples collected during the follow-up (p<0.001). There was a negative correlation between serum C5a levels and the number of days from symptom onset (p<0.001). C5a levels also correlated with a previously validated clinical risk score (p<0.001), and was associated with the severity of the disease (p<0.001). An overall reduction of C5a levels was observed after hospital discharge. However, elevated C5a levels persisted in those patients with high COVID-19 severity (i.e. those with a longest stay in the hospital), even after months from hospital discharge (p=0.020). Moreover, high C5a levels appeared to be associated with the presence of long-term respiratory symptoms (p=0.004). In conclusion, serum C5a levels remain high in severe cases of COVID-19, and are associated with the presence of respiratory symptoms after hospital discharge. These results may suggest a role for C5a in the long-term effects of COVID-19 infection.
  • Autores: García Tobar, Laura; Villalba Esparza, María; Abengozar Muela, Marta; et al.
    Revista: CYTOPATHOLOGY
    ISSN: 0956-5507 Vol.32 N° 5 2021 págs. 611 - 616
    Resumen
    Objective Understanding the immune environment of non-small cell lung cancer (NSCLC) is important for designing effective anticancer immunotherapies. We describe the use of multiplex immunofluorescence (mIF) assays to enable characterisation of the tumour-infiltrating immune cells and their interactions, both across and within immune subtypes. Methods Six cytological samples of NSCLC taken by transoesophageal ultrasound-guided fine needle aspiration were tested with an mIF assay designed to detect the expression of key immune cell markers such as CD3, CD8, CD20, CD11b, and CD68. Pan-cytokeratin was used to detect the NSCLC cells. Fluorescence images were acquired on a Vectra-Polaris Automated Quantitative Pathology Imaging System (Akoya Biosciences). Results MIF assay was able to reliably detect and quantify the myeloid cell markers CD11b, CD68, CD3+ and CD8+ T cells, and CD20+ B lymphocytes on cytological samples of NSCLC. Whole-tissue analysis and its correlation with the corresponding H&E stains allowed a better understanding of the tissue morphology and the relationship between tumour and stroma compartments. Additionally, a uniform, specific, and correct staining pattern was seen for every immune marker. Conclusion The implementation of mIF assay on cytological samples taken with minimally invasive methods seems feasible and can be used to explore the immune environment of NSCLC.
  • Autores: Vilalta Lacarra, Anna; Rodríguez Remírez, María; López Erdozain, María Inés; et al.
    Revista: JOURNAL OF THORACIC ONCOLOGY
    ISSN: 1556-0864 Vol.16 N° 10 Supl. S 2021 págs. S1007 - S1008
  • Autores: Redín Cabodevilla, María Esther; Garmendia Iturbe, Irati; Lozano Moreda, Teresa; et al.
    Revista: JOURNAL OF THORACIC ONCOLOGY
    ISSN: 1556-0864 Vol.16 N° 10 2021 págs. S949 - S949
  • Autores: Juesas Iglesias, L.; Sánchez Canteli, M.; Redin Resano, E.; et al.
    Revista: ORAL ONCOLOGY
    ISSN: 1368-8375 Vol.118 2021
  • Autores: Osarogiagbon, R.; Nishimura, K.; Rami Porta, R.; et al.
    Revista: JOURNAL OF THORACIC ONCOLOGY
    ISSN: 1556-0864 Vol.16 N° 10 2021 págs. S857 - S858
  • Autores: Valencia Leoz, Karmele; Bértolo Martín de Rosales, Cristina María; Sainz, C.; et al.
    Revista: JOURNAL OF THORACIC ONCOLOGY
    ISSN: 1556-0864 Vol.16 N° 10 2021 págs. S972 - S973
  • Autores: García Moure, Marc; Gállego Pérez de Larraya, Jaime; Patiño García, Ana; et al.
    Revista: NEURO-ONCOLOGY
    ISSN: 1522-8517 Vol.23 N° Supl. 1 2021 págs. 47
  • Autores: Moreno, H.; Ruiz Fernández de Córdoba, Francisco de Borja; Zandueta Pascual, Carolina; et al.
    Revista: CANCER RESEARCH
    ISSN: 0008-5472 Vol.81 N° 13 Supl. S 2021
  • Autores: Rubio Díaz-Cordoves, Ángel (Autor de correspondencia)
    Revista: EBIOMEDICINE
    ISSN: 2352-3964 Vol.51 2020 págs. UNSP 102577
  • Autores: Rolfe, B. E. (Autor de correspondencia); Pio Osés, Rubén; Woodruff, T. M.; et al.
    Revista: FRONTIERS IN IMMUNOLOGY
    ISSN: 1664-3224 Vol.11 2020 págs. 139
  • Autores: Macaya, I. ; Entrialgo-Cadierno, R.; Valencia Leoz, Karmele; et al.
    Revista: JOURNAL OF THORACIC ONCOLOGY
    ISSN: 1556-0864 Vol.15 N° 3 2020 págs. 311 - 313
  • Autores: Montuenga Badía, Luis (Autor de correspondencia); Zulueta Frances, Javier Joseph
    Revista: ANALES DEL SISTEMA SANITARIO DE NAVARRA
    ISSN: 1137-6627 Vol.43 N° 2 2020 págs. 131 - 139
  • Autores: Anguiano, M.; Morales, X. ; Castilla Ruíz, Carlos; et al.
    Revista: PLOS ONE
    ISSN: 1932-6203 Vol.15 N° 1 2020
    Resumen
    The migration of cancer cells is highly regulated by the biomechanical properties of their local microenvironment. Using 3D scaffolds of simple composition, several aspects of cancer cell mechanosensing (signal transduction, EMC remodeling, traction forces) have been separately analyzed in the context of cell migration. However, a combined study of these factors in 3D scaffolds that more closely resemble the complex microenvironment of the cancer ECM is still missing. Here, we present a comprehensive, quantitative analysis of the role of cell-ECM interactions in cancer cell migration within a highly physiological environment consisting of mixed Matrigel-collagen hydrogel scaffolds of increasing complexity that mimic the tumor microenvironment at the leading edge of cancer invasion. We quantitatively show that the presence of Matrigel increases hydrogel stiffness, which promotes beta 1 integrin expression and metalloproteinase activity in H1299 lung cancer cells. Then, we show that ECM remodeling activity causes matrix alignment and compaction that favors higher tractions exerted by the cells. However, these traction forces do not linearly translate into increased motility due to a biphasic role of cell adhesions in cell migration: at low concentration Matrigel promotes migration-effective tractions exerted through a high number of small sized focal adhesions. However, at high Matrigel concentration, traction forces are exerted through fewer, but larger focal adhesions that favor attachment yielding lower cell motility.
  • Autores: Matsuoka, K.; Bakiri, L.; Wolff, L. I.; et al.
    Revista: CELL RESEARCH
    ISSN: 1001-0602 Vol.30 N° 10 2020 págs. 885 - 901
    Resumen
    Osteosarcoma (OS) is the most frequent primary malignant bone tumor in urgent need of better therapies. Using genetically modified mouse models (GEMMs), we demonstrate that Wnt signaling promotes c-Fos-induced OS formation via the actions of the collagen-modifying enzyme Loxl2. c-Fos/AP-1 directly regulates the expression of the Wnt ligandsWnt7bandWnt9ain OS cells through promoter binding, and Wnt7b and Wnt9a in turn promote Loxl2 expression in murine and human OS cells through the transcription factors Zeb1 and Zeb2. Concordantly, inhibition of Wnt ligand secretion by inactivating theWnt-less(Wls)gene in osteoblasts in c-Fos GEMMs either early or in a therapeutic setting reduces Loxl2 expression and progression of OS. Wls-deficient osteosarcomas proliferate less, are less mineralized and are enriched in fibroblastic cells surrounded by collagen fibers. Importantly, Loxl2 inhibition using either the pan-Lox inhibitor BAPN or a specific inducible shRNA reduces OS cell proliferation in vitro and decreases tumor growth and lung colonization in murine and human orthotopic OS transplantation models. Finally, OS development is delayed in c-Fos GEMMs treated with BAPN or with specific Loxl2 blocking antibodies. Congruently, a strong correlation between c-FOS, LOXL2 and WNT7B/WNT9A expression is observed in human OS samples, and c-FOS/LOXL2 co-expression correlates with OS aggressiveness and decreased patient survival. Therefore, therapeutic targeting of Wnt and/or Loxl2 should be considered to potentiate the inadequate current treatments for pediatric, recurrent, and metastatic OS.
  • Autores: Peinado, P.; Andrades, A.; Cuadros, M.; et al.
    Revista: CANCERS
    ISSN: 2072-6694 Vol.12 N° 12 2020
    Resumen
    Simple Summary Mammalian SWI/SNF complexes regulate gene expression by reorganizing the way DNA is packaged into chromatin. SWI/SNF subunits are recurrently altered in tumors at multiple levels, including DNA mutations as well as alteration of the levels of RNA and protein. Cancer cell lines are often used to study SWI/SNF function, but their patterns of SWI/SNF alterations can be complex. Here, we present a comprehensive characterization of DNA mutations and RNA and protein expression of SWI/SNF members in 38 lung adenocarcinoma (LUAD) cell lines. We show that over 85% of our cell lines harbored at least one alteration in one SWI/SNF subunit. In addition, over 75% of our cell lines lacked expression of at least one SWI/SNF subunit at the protein level. Our catalog will help researchers choose an appropriate cell line model to study SWI/SNF function in LUAD. Mammalian SWI/SNF (SWitch/Sucrose Non-Fermentable) complexes are ATP-dependent chromatin remodelers whose subunits have emerged among the most frequently mutated genes in cancer. Studying SWI/SNF function in cancer cell line models has unveiled vulnerabilities in SWI/SNF-mutant tumors that can lead to the discovery of new therapeutic drugs. However, choosing an appropriate cancer cell line model for SWI/SNF functional studies can be challenging because SWI/SNF subunits are frequently altered in cancer by various mechanisms, including genetic alterations and post-transcriptional mechanisms. In this work, we combined genomic, transcriptomic, and proteomic approaches to study the mutational status and the expression levels of the SWI/SNF subunits in a panel of 38 lung adenocarcinoma (LUAD) cell lines. We found that the SWI/SNF complex was mutated in more than 76% of our LUAD cell lines and there was a high variability in the expression of the different SWI/SNF subunits. These results underline the importance of the SWI/SNF complex as a tumor suppressor in LUAD and the difficulties in defining altered and unaltered cell models for the SWI/SNF complex. These findings will assist researchers in choosing the most suitable cellular models for their studies of SWI/SNF to bring all of its potential to the development of novel therapeutic applications.
  • Autores: Quintanal-Villalonga, A.; Ferrer, I.; Guruceaga Martínez, Elisabet; et al.
    Revista: EBIOMEDICINE
    ISSN: 2352-3964 Vol.53 2020
    Resumen
    Background: Fibroblast growth factor receptor (FGFR)1 and FGFR4 have been associated with tumorigenesis in a variety of tumour types. As a therapeutic approach, their inhibition has been attempted in different types of malignancies, including lung cancer, and was initially focused on FGFR1-amplified tumours, though with limited success. Methods: In vitro and in vivo functional assessments of the oncogenic potential of downregulated/overexpressed genes in isogenic cell lines were performed, as well as inhibitor efficacy tests in vitro and in vivo in patient-derived xenografts (PDXs). mRNA was extracted from FFPE non-small cell lung cancer samples to determine the prognostic potential of the genes under study. Findings: We provide in vitro and in vivo evidence showing that expression of the adhesion molecule N-cadherin is key for the oncogenic role of FGFR1/4 in non-small cell lung cancer. According to this, assessment of the expression of genes in different lung cancer patient cohorts showed that FGFR1 or FGFR4 expression alone showed no prognostic potential, and that only co-expression of FGFR1 and/or FGFR4 with N-cadherin inferred a poorer outcome. Treatment of high-FGFR1 and/or FGFR4-expressing lung cancer cell lines and patient-derived xenografts with selective FGFR inhibitors showed high efficacy, but only in models with high FGFR1/4 and N-cadherin expression. Interpretation: Our data show that the determination of the expression of FGFR1 or FGFR4 alone is not sufficient to predict anti-FGFR therapy efficacy; complementary determination of N-cadherin expression may further optimise patient selection for this therapeutic strategy. (c) 2020 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license. (http://creativecommons.org/licenses/by-nc-nd/4.0/)
  • Autores: Ajona Martínez-Polo, Daniel; Ortiz Espinosa, Sergio; Lozano Moreda, Teresa; et al.
    Revista: NATURE CANCER
    ISSN: 2662-1347 Vol.1 2020 págs. 75 - 85
    Resumen
    Harnessing the immune system by blocking the programmed cell death protein 1 (PD-1) pathway has been a major breakthrough in non-small-cell lung cancer treatment. Nonetheless, many patients fail to respond to PD-1 inhibition. Using three syngeneic models, we demonstrate that short-term starvation synergizes with PD-1 blockade to inhibit lung cancer progression and metastasis. This antitumor activity was linked to a reduction in circulating insulin-like growth factor 1 (IGF-1) and a downregulation of IGF-1 receptor (IGF-1R) signaling in tumor cells. A combined inhibition of IGF-1R and PD-1 synergistically reduced tumor growth in mice. This effect required CD8 cells, boosted the intratumoral CD8/Treg ratio and led to the development of tumor-specific immunity. In patients with non-small-cell lung cancer, high plasma levels of IGF-1 or high IGF-1R expression in tumors was associated with resistance to anti-PD-1¿programmed death-ligand 1 immunotherapy. In conclusion, our data strongly support the clinical evaluation of IGF-1 modulators in combination with PD-1 blockade.
  • Autores: Novacek, V.; McGauran, G.; Matallanas, D.; et al.
    Revista: PLOS COMPUTATIONAL BIOLOGY
    ISSN: 1553-734X Vol.16 N° 12 2020
    Resumen
    Author summary LinkPhinder is a new approach to prediction of protein signalling networks based on kinase-substrate relationships that outperforms existing approaches. Phosphorylation networks govern virtually all fundamental biochemical processes in cells, and thus have moved into the centre of interest in biology, medicine and drug development. Fundamentally different from current approaches, LinkPhinder is inherently network-based and makes use of the most recent AI developments. We represent existing phosphorylation data as knowledge graphs, a format for large-scale and robust knowledge representation. Training a link prediction model on such a structure leads to novel, biologically valid phosphorylation network predictions that cannot be made with competing tools. Thus our new conceptual approach can lead to establishing a new niche of AI applications in computational biology. Phosphorylation of specific substrates by protein kinases is a key control mechanism for vital cell-fate decisions and other cellular processes. However, discovering specific kinase-substrate relationships is time-consuming and often rather serendipitous. Computational predictions alleviate these challenges, but the current approaches suffer from limitations like restricted kinome coverage and inaccuracy. They also typically utilise only local features without reflecting broader interaction context. To address these limitations, we have developed an alternative predictive model. It uses statistical relational learning on top of phosphorylation networks interpreted as knowledge graphs, a simple yet robust model for representing networked knowledge. Compared to a representative selection of six existing systems, our model has the highest kinome coverage and produces biologically valid high-confidence predictions not possible with the other tools. Specifically, we have experimentally validated predictions of previously unknown phosphorylations by the LATS1, AKT1, PKA and MST2 kinases in human. Thus, our tool is useful for focusing phosphoproteomic experiments, and facilitates the discovery of new phosphorylation reactions. Our model can be accessed publicly via an easy-to-use web interface (LinkPhinder).
  • Autores: Sánchez-Canteli, M.; Granda-Diaz, R.; del Río-Ibisate, N.; et al.
    Revista: CANCER IMMUNOLOGY IMMUNOTHERAPY
    ISSN: 0340-7004 Vol.69 N° 10 2020 págs. 2089 - 2100
    Resumen
    Introduction The importance of immune tumor microenvironment in the prognosis of patients with head and neck squamous carcinomas (HNSCC) is increasingly recognized. We analyzed the prognostic relevance of PD-L1 and PD-1 expressions in relation to the infiltration by CD8(+) and FOXP3(+) tumor-infiltrating lymphocytes (TILs). Methods Samples from 372 surgically treated HPV-negative HNSCC patients were evaluated by immunohistochemistry for PD-L1 expression [both tumor proportion score (TPS) and combined proportion score (CPS)], PD-1 expression in immune cells, and density of infiltrating CD8(+) and FOXP3(+) TILs. PD-L1 expression and CD8(+) TIL density were combined to establish the type of tumor microenvironment. Results 29.5% cases exhibited PD-L1 TPS positivity (>= 1%), whereas PD-L1 CPS positivity (>= 1%) was observed in 40% cases. 47.5% cases showed positive PD-1 expression (>= 1%). PD-L1 and PD-1 positivity correlated with a high density of both CD8(+) and FOXP3(+) TILs. In univariate analysis, PD-L1 TPS positivity (P = 0.026), PD-L1 CPS positivity (P = 0.004), high density of CD8(+) TIL (P = 0.001), and high density of FOXP3(+) TIL (P = 0.004) were associated with a better disease-specific survival (DSS). However, in multivariate analysis, only high density of CD8(+) TIL was associated with a better DSS (P = 0.002). The type of tumor microenvironment correlated with DSS (P = .008), with the better DSS observed in cases with type I (PD-L1 CPS positivity and high density of CD8(+) TIL). Conclusions High infiltration by CD8(+) TIL is associated with better survival outcomes. Positive PD-L1 expression correlates with a high infiltration by TILs, explaining its association with better prognosis.
  • Autores: Abengozar Muela, Marta; Villalba Esparza, María; García Ros, David; et al.
    Revista: MODERN PATHOLOGY
    ISSN: 0893-3952 Vol.33 N° 12 2020 págs. 2507 - 2519
    Resumen
    The precise nature of the local immune responses in lung tuberculosis (TB) granulomas requires a comprehensive understanding of their environmental complexities. At its most basic level, a granuloma is a compact, organized immune aggregate of macrophages surrounded by myeloid, B and T cells. We established two complementary multiplex immunolabeling panels to simultaneously evaluate the myeloid and lymphocytic contexture of 14 human lung TB granulomas in formalin-fixed paraffin-embedded tissue samples. We observed diverse CD3+ and CD8+ T-cell and CD20+ B lymphocyte compositions of the granuloma immune environment and a relatively homogeneous distribution of all myeloid cells. We also found significant associations between CD8+ T-cell densities and the myeloid marker CD11b and phagocytic cell marker CD68. In addition, significantly more CD68+ macrophages and CD8+ T cells were found inMycobacterium tuberculosis-infected granulomas, as detected by Ziehl-Neelsen staining. FOXP3 expression was predominately found in a small subset of CD4+ T cells in different granulomas. As the success or failure of each granuloma is determined by the immune response within that granuloma at a local and not a systemic level, we attempted to identify the presence of reactive T cells based on expression of the T-cell activation marker CD137 (4-1BB) and programmed cell death-1 (PD-1). Only a small fraction of the CD4+ and CD8+ T cells expressed PD-1. CD137 expression was found only in a very small fra
  • Autores: Serrano Tejero, Diego; Cordero, G. ; Kawamura, R. ; et al.
    Revista: MOLECULAR CELL
    ISSN: 1097-2765 Vol.80 N° 6 2020 págs. 1025 - 1038
    Resumen
    The structural organization of chromosomes is a crucial feature that defines the functional state of genes and genomes. The extent of structural changes experienced by genomes of eukaryotic cells can be dramatic and spans several orders of magnitude. At the core of these changes lies a unique group of ATPases-the SMC proteins-that act as major effectors of chromosome behavior in cells. The Smc5/6 proteins play essential roles in the maintenance of genome stability, yet their mode of action is not fully understood. Here we show that the human Smc5/6 complex recognizes unusual DNA configurations and uses the energy of ATP hydrolysis to promote their compaction. Structural analyses reveal subunit interfaces responsible for the functionality of the Smc5/6 complex and how mutations in these regions may lead to chromosome breakage syndromes in humans. Collectively, our results suggest that the Smc5/6 complex promotes genome stability as a DNA micro-compaction machine.
  • Autores: Carazo Melo, Fernando; Bértolo Martín de Rosales, Cristina María; Castilla Ruíz, Carlos; et al.
    Revista: CANCERS
    ISSN: 2072-6694 Vol.12 N° 7 2020
    Resumen
    The development of predictive biomarkers of response to targeted therapies is an unmet clinical need for many antitumoral agents. Recent genome-wide loss-of-function screens, such as RNA interference (RNAi) and CRISPR-Cas9 libraries, are an unprecedented resource to identify novel drug targets, reposition drugs and associate predictive biomarkers in the context of precision oncology. In this work, we have developed and validated a large-scale bioinformatics tool named DrugSniper, which exploits loss-of-function experiments to model the sensitivity of 6237 inhibitors and predict their corresponding biomarkers of sensitivity in 30 tumor types. Applying DrugSniper to small cell lung cancer (SCLC), we identified genes extensively explored in SCLC, such as Aurora kinases or epigenetic agents. Interestingly, the analysis suggested a remarkable vulnerability to polo-like kinase 1 (PLK1) inhibition inCREBBP-mutant SCLC cells. We validated this association in vitro using four mutated and four wild-type SCLC cell lines and twoPLK1inhibitors (Volasertib and BI2536), confirming that the effect ofPLK1inhibitors depended on the mutational status ofCREBBP. Besides, DrugSniper was validated in-silico with several known clinically-used treatments, including the sensitivity of Tyrosine Kinase Inhibitors (TKIs) and Vemurafenib toFLT3andBRAFmutant cells, respectively. These findings show the potential of genome-wide loss-of-function screens to identify new personalized therapeutic hypotheses in SCLC and potentially in other tumors, which is a valuable starting point for further drug development and drug repositioning projects.
  • Autores: Pros, E.; Saigi, M.; Alameda Serrano, Daniel; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN: 0923-7534 Vol.31 N° 2 2020 págs. 274 - 282
    Resumen
    BACKGROUND: The etiology and the molecular basis of lung adenocarcinomas (LuADs) in nonsmokers are currently unknown. Furthermore, the scarcity of available primary cultures continues to hamper our biological understanding of non-smoking-related lung adenocarcinomas (NSK-LuADs). PATIENTS AND METHODS: We established patient-derived cancer cell (PDC) cultures from metastatic NSK-LuADs, including two pairs of matched EGFR-mutant PDCs before and after resistance to tyrosine kinase inhibitors (TKIs), and then performed whole-exome and RNA sequencing to delineate their genomic architecture. For validation, we analyzed independent cohorts of primary LuADs. RESULTS: In addition to known non-smoker-associated alterations (e.g. RET, ALK, EGFR, and ERBB2), we discovered novel fusions and recurrently mutated genes, including ATF7IP, a regulator of gene expression, that was inactivated in 5% of primary LuAD cases. We also found germline mutations at dominant familiar-cancer genes, highlighting the importance of genetic predisposition in the origin of a subset of NSK-LuADs. Furthermore, there was an over-representation of inactivating alterations at RB1, mostly through complex intragenic rearrangements, in treatment-naive EGFR-mutant LuADs. Three EGFR-mutant and one EGFR-wild-type tumors acquired resistance to EGFR-TKIs and chemotherapy, respectively, and histology on re-biopsies revealed the development of small-cell lung cancer/squamous cell carcinoma (SCLC/LuSCC) transformation. These features were consistent with RB1 inactivation and acquired EGFR-T790M mutation or FGFR3-TACC3 fusion in EGFR-mutant tumors. CONCLUSIONS: We found recurrent alterations in LuADs that deserve further exploration. Our work also demonstrates that a subset of NSK-LuADs arises within cancer-predisposition syndromes. The preferential occurrence of RB1 inactivation, via complex rearrangements, found in EGFR-mutant tumors appears to favor SCLC/LuSCC transformation under growth-inhibition pressures. Thus RB1 inactivation may predict the risk of LuAD transformation to a more aggressive type of lung cancer, and may need to be considered as a part of the clinical management of NSK-LuADs patients.
  • Autores: Rodriguez-Pena, A.; Uranga-Solchaga, J.; Ortiz de Solórzano Aurusa, Carlos; et al.
    Revista: SCIENTIFIC REPORTS
    ISSN: 2045-2322 Vol.10 N° 1 2020 págs. 2779
    Resumen
    3D cell culture models consisting of self-assembled tumour cells in suspension, commonly known as tumour spheroids, are becoming mainstream for high-throughput anticancer drug screening. A usual measurable outcome of screening studies is the growth rate of the spheroids in response to treatment. This is commonly quantified on images obtained using complex, expensive, optical microscopy systems, equipped with high-quality optics and customized electronics. Here we present a novel, portable, miniaturized microscope made of low-cost, mass-producible parts, which produces both fluorescence and phase-gradient contrast images. Since phase-gradient contrast imaging is based on oblique illumination, epi-illumination is used for both modalities, thus simplifying the design of the system. We describe the system, characterize its performance on synthetic samples and show proof-of-principle applications of the system consisting in imaging and monitoring the formation and growth of lung and pancreas cancer tumour spheroids within custom made microfluidic devices.
  • Autores: Lozano Escario, María Dolores; Abengozar Muela, Marta; Alvarez, M.; et al.
    Revista: LABORATORY INVESTIGATION
    ISSN: 0023-6837 Vol.100 N° Supl. 1 2020 págs. 390 - 391
  • Autores: Íñigo Marco, Ignacio; González Huarriz, María Soledad; García Moure, Marc; et al.
    Revista: NEURO-ONCOLOGY
    ISSN: 1522-8517 Vol.22 2020 págs. 473 - 473
  • Autores: Ajona Martínez-Polo, Daniel; Ortiz Espinosa, Sergio; Pio Osés, Rubén (Autor de correspondencia); et al.
    Revista: FRONTIERS IN IMMUNOLOGY
    ISSN: 1664-3224 Vol.10 2019
    Resumen
    The complement system represents a pillar of the innate immune response. This system, critical for host defense against pathogens, encompasses more than 50 soluble, and membrane-bound proteins. Emerging evidence underscores its clinical relevance in tumor progression and its role in metastasis, one of the hallmarks of cancer. The multistep process of metastasis entails the acquisition of advantageous functions required for the formation of secondary tumors. Thus, targeting components of the complement system could impact not only on tumor initiation but also on several crucial steps along tumor dissemination. This novel vulnerability could be concomitantly exploited with current strategies overcoming tumor-mediated immunosuppression to provide a substantial clinical bene fit in the treatment of metastatic disease. In this review, we offer a tour d'horizon on recent advances in this area and their prospective potential for cancer treatment.
  • Autores: Pio Osés, Rubén (Autor de correspondencia); Ajona Martínez-Polo, Daniel; Ortiz Espinosa, Sergio; et al.
    Revista: FRONTIERS IN IMMUNOLOGY
    ISSN: 1664-3224 Vol.10 2019 págs. 774
    Resumen
    Reactivation of cytotoxic CD8(+) T-cell responses has set a new direction for cancer immunotherapy. Neutralizing antibodies targeting immune checkpoint programmed cell death protein 1 (PD-1) or its ligand (PD-L1) have been particularly successful for tumor types with limited therapeutic options such as melanoma and lung cancer. However, reactivation of T cells is only one step toward tumor elimination, and a substantial fraction of patients fails to respond to these therapies. In this context, combination therapies targeting more than one of the steps of the cancer-immune cycle may provide significant benefits. To find the best combinations, it is of upmost importance to understand the interplay between cancer cells and all the components of the immune response. This review focuses on the elements of the complement system that come into play in the cancer-immunity cycle. The complement system, an essential part of innate immunity, has emerged as a major regulator of cancer immunity. Complement effectors such as C1q, anaphylatoxins C3a and C5a, and their receptors C3aR and C5aR1, have been associated with tolerogenic cell death and inhibition of antitumor T-cell responses through the recruitment and/or activation of immunosuppressive cell subpopulations such as myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), or M2 tumor-associated macrophages (TAMs). Evidence is provided to support the idea that complement blocks many of the effector routes associated with the cancer-immunity cycle, providing the rationale for new therapeutic combinations aimed to enhance the antitumor efficacy of anti-PD-1/PD-L1 checkpoint inhibitors.
  • Autores: Vicent Cambra, Silvestre; Lieshout, R.; Saborowski, A.; et al.
    Revista: LIVER INTERNATIONAL
    ISSN: 1478-3223 Vol.39 N° Supl. 1 2019 págs. 79 - 97
    Resumen
    Human cholangiocarcinoma (CCA) is an aggressive tumour entity arising from the biliary tree, whose molecular pathogenesis remains largely undeciphered. Over the last decade, the advent of high-throughput and cell-based techniques has significantly increased our knowledge on the molecular mechanisms underlying this disease while, at the same time, unravelling CCA complexity. In particular, it becomes clear that CCA displays pronounced inter- and intratumoural heterogeneity, which is presumably the consequence of the interplay between distinct tissues and cells of origin, the underlying diseases, and the associated molecular alterations. To better characterize these events and to design novel and more effective therapeutic strategies, a number of CCA experimental and preclinical models have been developed and are currently generated. This review summarizes the current knowledge and understanding of these models, critically underlining their translational usefulness and limitations. Furthermore, this review aims to provide a comprehensive overview on cells of origin, cancers stem cells and their dynamic interplay within CCA tissue.
  • Autores: Seijo Maceiras, Luis Miguel; Peled, N.; Ajona Martínez-Polo, Daniel; et al.
    Revista: JOURNAL OF THORACIC ONCOLOGY
    ISSN: 1556-0864 Vol.14 N° 3 2019 págs. 343 - 357
    Resumen
    The present review is an update of the research and development efforts regarding the use of molecular biomarkers in the lung cancer screening setting. The two main unmet clinical needs, namely, the refinement of risk to improve the selection of individuals undergoing screening and the characterization of undetermined nodules found during the computed tomography-based screening process are the object of the biomarkers described in the present review. We first propose some principles to optimize lung cancer biomarker discovery projects. Then, we summarize the discovery and developmental status of currently promising molecular candidates, such as autoantibodies, complement fragments, microRNAs, circulating tumor DNA, DNA methylation, blood protein profiling, or RNA airway or nasal signatures. We also mention other emerging biomarkers or new technologies to follow, such as exhaled breath biomarkers, metabolomics, sputum cell imaging, genetic predisposition studies, and the integration of next-generation sequencing into study of circulating DNA. We also underline the importance of integrating different molecular technologies together with imaging, radiomics, and artificial intelligence. We list a number of completed, ongoing, or planned trials to show the clinical utility of molecular biomarkers. Finally, we comment on future research challenges in the field of biomarkers in the context of lung cancer screening and propose a design of a trial to test the clinical utility of one or several candidate biomarkers. (C) 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
  • Autores: Ajona Martínez-Polo, Daniel; Ortiz Espinosa, Sergio; Pio Osés, Rubén (Autor de correspondencia)
    Revista: SEMINARS IN CELL AND DEVELOPMENTAL BIOLOGY
    ISSN: 1084-9521 Vol.85 2019 págs. 153 - 163
    Resumen
    Recent insights into the role of complement anaphylatoxins C3a and C5a in cancer provide new opportunities for the development of innovative biomarkers and therapeutic strategies. These two complement activation products can maintain chronic inflammation, promote an immunosuppressive microenvironment, induce angiogenesis, and increase the motility and metastatic potential of cancer cells. Still, the diverse heterogeneity of responses mediated by these peptides poses a challenge both to our understanding of the role played by these molecules in cancer progression and to the development of effective treatments. This review attempts to summarize the evidence surrounding the involvement of anaphylatoxins in the biological contexts associated with tumor progression. We also describe the recent developments that support the inhibition of anaphylatoxins, or their cognate receptors C3aR and C5aRI, as a treatment option for maximizing the clinical efficacy of current immunotherapies that target the PD-1/PD-L1 immune checkpoint. (C) 2017 Elsevier Ltd. All rights reserved.
  • Autores: Erice, O.; Vallejo Blanco, Adrián; Ponz Sarvisé, Mariano; et al.
    Revista: CANCERS
    ISSN: 2072-6694 Vol.11 N° 12 2019 págs. 1868
    Resumen
    Cholangiocarcinoma (CCA) is a genetically and histologically complex disease with a highly dismal prognosis. A deeper understanding of the underlying cellular and molecular mechanisms of human CCA will increase our current knowledge of the disease and expedite the eventual development of novel therapeutic strategies for this fatal cancer. This endeavor is effectively supported by genetic mouse models, which serve as sophisticated tools to systematically investigate CCA pathobiology and treatment response. These in vivo models feature many of the genetic alterations found in humans, recapitulate multiple hallmarks of cholangiocarcinogenesis (encompassing cell transformation, preneoplastic lesions, established tumors and metastatic disease) and provide an ideal experimental setting to study the interplay between tumor cells and the surrounding stroma. This review is intended to serve as a compendium of CCA mouse models, including traditional transgenic models but also genetically flexible approaches based on either the direct introduction of DNA into liver cells or transplantation of pre-malignant cells, and is meant as a resource for CCA researchers to aid in the selection of the most appropriate in vivo model system.
  • Autores: Mastellos, D. C.; Blom, A. M. ; Connolly, E. S.; et al.
    Revista: NATURE IMMUNOLOGY
    ISSN: 1529-2908 Vol.20 N° 11 2019 págs. 1409 - 1413
  • Autores: Grávalos, C. (Autor de correspondencia); Sanmartín, O.; Gurpide Ayarra, Luis Alfonso; et al.
    Revista: CLINICAL AND TRANSLATIONAL ONCOLOGY
    ISSN: 1699-048X Vol.21 N° 5 2019 págs. 556 - 571
    Resumen
    Progress in the understanding of many tumors has enabled the development of new therapies, such as those targeted at specific molecules involved in cell growth (targeted therapies) or intended to modulate the immune system (immunotherapy). However, along with the clinical benefit provided by these new treatments, new adverse effects have also appeared. Dermatological toxicities such as papulopustular eruptions, xerosis, and pruritus are common with EGFR inhibitors. Other adverse effects have also been described with PDGFR, BCR-ABL, and MAPK tyrosine kinase inhibitors, antiangiogenic drugs, and inhibitors at immune checkpoints such as CTLA-4 and PD-1/PD-L1. Onset of these adverse effects often causes dose reductions and/or delays in administering the prescribed therapy, which can affect patient survival and quality of life. It is, therefore, important to prevent the occurrence of these adverse effects, or to treat unavoidable ones as soon as possible. This requires cooperation between medical oncologists and dermatologists. This article reviews the various dermatological toxicities associated with targeted therapies and immunotherapies, along with their diagnosis and therapeutic management.
  • Autores: de Prado, J.; Sanchez, M. (Autor de correspondencia); Calvo González, Alfonso; et al.
    Revista: FUSION ENGINEERING AND DESIGN
    ISSN: 0920-3796 Vol.146 2019 págs. 1810 - 1813
    Resumen
    The present work proposes a brazing procedure to join a self-passivating tungsten alloy (W-10Cr-0.5Y) with Eurofer. The results indicated the achievement of high continuity W-Eurofer joints using 80Cu-20Ti filler material, which involves operative brazeability. The resulting microstructure of the braze changes considerably compared to the brazing attempts with pure tungsten, which is associated to the reactive character of chromium. A high interaction between molten filler and W base material close to the braze was detected, with preferential grain boundary penetration of Cu-Ti into W alloy. It gave rise to a loss of hardness at the W base material near the joint. Regarding to the strength of the joints, shear strength of similar to 90 MPa was obtained.
  • Autores: Ariz Galilea, Mikel; Abad, R. C. ; Castellanos, G. ; et al.
    Revista: IEEE TRANSACTIONS ON MEDICAL IMAGING
    ISSN: 0278-0062 Vol.38 N° 3 2019 págs. 813 - 823
    Resumen
    We present a dynamic atlas composed of neuromelanin-enhancedmagnetic resonance brain images of 40 healthy subjects. The performance of this atlas is evaluated on the fully automated segmentation of two paired neuromelanin-rich brainstem healthy structures: the substantia nigra pars compacta and the locus coeruleus. We show that our dynamic atlas requires in average 60% less images and, therefore, 60% less computation time than a static multi-image atlas while achieving a similar segmentation performance. Then, we show that by applying our dynamic atlas, composed of healthy subjects, to the segmentation and neuromelanin quantification of a set of brain images of 39 Parkinson disease patients, we are able to find significant quantitative differences in the level of neuromelanin between healthy subjects and Parkinson disease patients, thus opening the door to the use of these structures as image biomarkers in future computer aided diagnosis systems for the diagnosis of Parkinson disease.
  • Autores: Villalba Esparza, María; Redín Cabodevilla, María Esther; Expósito Rincón, Francisco; et al.
    Revista: SCIENTIFIC REPORTS
    ISSN: 2045-2322 Vol.9 2019 págs. 15400
    Resumen
    Finding novel targets in non-small cell lung cancer (NSCLC) is highly needed and identification of synthetic lethality between two genes is a new approach to target NSCLC. We previously found that TMPRSS4 promotes NSCLC growth and constitutes a prognostic biomarker. Here, through large-scale analyses across 5 public databases we identified consistent co-expression between TMPRSS4 and DDR1. Similar to TMPRSS4, DDR1 promoter was hypomethylated in NSCLC in 3 independent cohorts and hypomethylation was an independent prognostic factor of disease-free survival. Treatment with 5-azacitidine increased DDR1 levels in cell lines, suggesting an epigenetic regulation. Cells lacking TMPRSS4 were highly sensitive to the cytotoxic effect of the DDR1 inhibitor dasatinib. TMPRSS4/DDR1 double knock-down (KD) cells, but not single KD cells suffered a G0/G1 cell cycle arrest with loss of E2F1 and cyclins A and B, increased p21 levels and a larger number of cells in apoptosis. Moreover, double KD cells were highly sensitized to cisplatin, which caused massive apoptosis (similar to 40%). In vivo studies demonstrated tumor regression in double KD-injected mice. In conclusion, we have identified a novel vulnerability in NSCLC resulting from a synthetic lethal interaction between DDR1 and TMPRSS4.
  • Autores: Fernández-Calver, A.; Euba, B.; Caballero, L.; et al.
    Revista: BIOMOLECULES
    ISSN: 2218-273X Vol.9 N° 12 2019 págs. 891
    Resumen
    Chronic obstructive pulmonary disease (COPD) is characterized by abnormal inflammation and impaired airway immunity, providing an opportunistic platform for nontypeable Haemophilus influenzae (NTHi) infection. In this context, therapies targeting not only overactive inflammation without significant adverse effects, but also infection are of interest. Increasing evidence suggests that polyphenols, plant secondary metabolites with anti-inflammatory and antimicrobial properties, may be protective. Here, a Cistus salviifolius plant extract containing quercetin, myricetin, and punicalagin was shown to reduce NTHi viability. Analysis of these polyphenols revealed that quercetin has a bactericidal effect on NTHi, does not display synergies, and that bacteria do not seem to develop resistance. Moreover, quercetin lowered NTHi airway epithelial invasion through a mechanism likely involving inhibition of Akt phosphorylation, and reduced the expression of bacterially-induced proinflammatory markers il-8, cxcl-1, il-6, pde4b, and tnf¿. We further tested quercetin's effect on NTHi murine pulmonary infection, showing a moderate reduction in bacterial counts and significantly reduced expression of proinflammatory genes, compared to untreated mice. Quercetin administration during NTHi infection on a zebrafish septicemia infection model system showed a bacterial clearing effect without signs of host toxicity. In conclusion, this study highlights the therapeutic potential of the xenohormetic molecule quercetin against NTHi infection.
  • Autores: Lozano Escario, María Dolores; Abengozar Muela, Marta; Echeveste, José Ignacio; et al.
    Revista: CANCER CYTOPATHOLOGY
    ISSN: 1934-662X Vol.127 N° 7 2019 págs. 470 - 480
    Resumen
    Background Programmed death-ligand 1 (PD-L1) expression, as assessed by immunohistochemistry (IHC), is used to select patients with non-small cell lung cancer (NSCLC) for anti-programmed cell death protein 1 (PD-1)/PD-L1 therapy. The current study evaluated the feasibility and efficacy of PD-L1 immunostaining and quantitation on direct Papanicolaou-stained cytological smears compared with formalin-fixed paraffin-embedded samples (cytological cell blocks and surgical resection specimens) in NSCLC cases using 2 commercially available assays: the PD-L1 IHC 22C3 pharmDx assay (Agilent Technologies/Dako, Carpinteria, CA, USA) and the Ventana SP263 Assay (Ventana Medical Systems Inc, Tucson, Arizona). Methods PD-L1 immunostaining using either both or one of the assays was tested in 117 sets of paired samples obtained from 62 NSCLC cases. The tumor proportion score was reported in every case following the recommendations of the International Association for the Study of Lung Cancer (IASLC). Results In 57 sets of samples, both PD-L1 assays were used. Due to the availability of samples, only 1 assay was performed in 3 sets of samples and in 2 cases, only cytology smears were used and tested for both assays. A total of 113 sets of paired samples finally were evaluated; 4 cases could not be studied due to intense nonspecific background staining. A significant concordance between the 2 assays on cytological smears was found. Concordance between paired cytological smears and formalin-fixed paraffin-embedded samples was observed in 97.3% of the cases. Conclusions The quantification of PD-L1 expression on direct Papanicolaou-stained cytology smears is feasible and reliable for both PD-L1 assays.
  • Autores: Garmendia, Irati; Pajares Villandiego, María José; Hermida-Prado, F.; et al.
    Revista: AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
    ISSN: 1073-449X Vol.200 N° 7 2019 págs. 888 - 899
    Resumen
    Rationale: The characterization of new genetic alterations is essential to assign effective personalized therapies in non-small cell lung cancer (NSCLC). Furthermore, finding stratification biomarkers is essential for successful personalized therapies. Molecular alterations of YES1, a member of the SRC (proto-oncogene tyrosine-protein kinase Src) family kinases (SFKs), can be found in a significant subset of patients with lung cancer.Objectives: To evaluate YES1 (v-YES-1 Yamaguchi sarcoma viral oncogene homolog 1) genetic alteration as a therapeutic target and predictive biomarker of response to dasatinib in NSCLC.Methods: Functional significance was evaluated by in vivo models of NSCLC and metastasis and patient-derived xenografts. The efficacy of pharmacological and genetic (CRISPR [clustered regularly interspaced short palindromic repeats]/Cas9 [CRISPR-associated protein 9]) YES1 abrogation was also evaluated. In vitro functional assays for signaling, survival, and invasion were also performed. The association between YES1 alterations and prognosis was evaluated in clinical samples.
  • Autores: Hermida-Prado, F. ; Granda-Diaz, R. ; del-Rio-Ibisate, N.; et al.
    Revista: CANCERS
    ISSN: 2072-6694 Vol.11 N° 11 2019
    Resumen
    Aberrant SRC expression and activation is frequently detected in multiple cancers, and hence, targeting SRC has emerged as a promising therapeutic strategy. Different SRC inhibitors have demonstrated potent anti-tumor activity in preclinical models, although they largely lack clinical efficacy as monotherapy in late-stage solid tumors, including head and neck squamous cell carcinomas (HNSCC). Adequate selection and stratification of patients who may respond to and benefit from anti-SRC therapies is therefore needed to guide clinical trials and treatment efficacy. This study investigates the prognostic significance of active SRC expression in a homogeneous cohort of 122 human papillomavirus (HPV)-negative, surgically treated HNSCC patients. Immunohistochemical evaluation of the active form of SRC by means of anti-SRC Clone 28 monoclonal antibody was specifically performed and subsequently correlated with clinical data. The expression of p-SRC (Tyr419), total SRC, and downstream SRC effectors was also analyzed. Our results uncovered striking differences in the prognostic relevance of SRC expression in HNSCC patients depending on the tumor site. Active SRC expression was found to significantly associate with advanced disease stages, presence of lymph node metastasis, and tumor recurrences in patients with laryngeal tumors, but not in the pharyngeal subgroup. Multivariate Cox analysis further revealed active SRC expression as an independent predictor of cancer-specific mortality in patients with laryngeal carcinomas. Concordantly, expression of p-SRC (Tyr419) and the SRC substrates focal adhesion kinase (FAK) and the Arf GTPase-activating protein ASAP1 also showed specific associations with poor prognosis in the larynx. These findings could have important implications in ongoing Src family kinase (SFK)-based clinical trials, as these new criteria could help to improve patient selection and develop biomarker-stratified trials.
  • Autores: Sanmartin, O.; Beato, C.; Suh-Oh, H. J.; et al.
    Revista: ACTAS DERMO-SIFILIOGRAFICAS
    ISSN: 0001-7310 Vol.110 N° 6 2019 págs. 448 - 459
    Resumen
    Although the arrival of new chemotherapy drugs and combinations has brought progress in terms of cancer patient survival, they entail many adverse effects that can compromise treatment, and hence prognosis, of the disease. Cytostatic agents can cause dermatological toxicity, among other side effects. The most familiar adverse effect of chemotherapy is alopecia. Although not serious, this changes the outward appearance of cancer patients. Other adverse effects include hypersensitivity and photosensitivity reactions, hand-foot syndrome, epidermal necrolysis, recall reactions, scleroderma-like reactions, Raynaud's phenomenon, eccrine squamous syringometaplasia, neutrophilic eccrine hidradenitis, nail abnormalities, pigmentation changes and extravasation injuries. Onset of these adverse effects often causes ose reduction and/or delayed treatment, which can affect patient survival and quality of life. It is therefore important to prevent their occurrence and treat them promptly, which requires cooperation between medical oncologists and dermatologists. This article reviews chemotherapy ssociated dermatological toxicity, along with its diagnosis and therapeuticmanagement. (C) 2019 AEDV. Published by Elsevier Espana, S.L.U. All rights reserved.
  • Autores: Villalba Esparza, María; Expósito Rincón, Francisco; Pajares Villandiego, María José; et al.
    Revista: JOURNAL OF CLINICAL MEDICINE
    ISSN: 2077-0383 Vol.8 N° 12 2019 págs. E2134
    Resumen
    Relapse rates in surgically resected non-small-cell lung cancer (NSCLC) patients are between 30% and 45% within five years of diagnosis, which shows the clinical need to identify those patients at high risk of recurrence. The eighth TNM staging system recently refined the classification of NSCLC patients and their associated prognosis, but molecular biomarkers could improve the heterogeneous outcomes found within each stage. Here, using two independent cohorts (MDA and CIMA-CUN) and the eighth TNM classification, we show that TMPRSS4 protein expression is an independent prognostic factor in NSCLC, particularly for patients at stage I: relapse-free survival (RFS) HR, 2.42 (95% CI, 1.47-3.99), p < 0.001; overall survival (OS) HR, 1.99 (95% CI, 1.25-3.16), p = 0.004). In stage IA, high levels of this protein remained associated with worse prognosis (p = 0.002 for RFS and p = 0.001 for OS). As TMPRSS4 expression is epigenetically regulated, methylation status could be used in circulating tumor DNA from liquid biopsies to monitor patients. We developed a digital droplet PCR (ddPCR) method to quantify absolute copy numbers of methylated and unmethylated CpGs within the TMPRSS4 and SHOX2 (as control) promoters in plasma and bronchoalveolar lavage (BAL) samples. In case-control studies, we demonstrated that TMPRSS4 hypomethylation can be used as a diagnostic tool in early stages, with an AUROC of 0.72 (p = 0.008; 91% specificity and 52% sensitivity) for BAL and 0.73 (p = 0.015; 65% specificity and 90% sensitivity) for plasma, in early stages. In conclusion, TMPRSS4 protein expression can be used to stratify patients at high risk of relapse/death in very early stages NSCLC patients. Moreover, analysis of TMPRSS4 methylation status by ddPCR in blood and BAL is feasible and could serve as a non-invasive biomarker to monitor surgically resected patients.
  • Autores: Carazo Melo, Fernando; Campuzano, L.; Cendoya Garmendia, Xabier; et al.
    Revista: GIGASCIENCE
    ISSN: 2047-217X Vol.8 N° 4 2019
    Resumen
    BACKGROUND: Aberrant alternative splicing plays a key role in cancer development. In recent years, alternative splicing has been used as a prognosis biomarker, a therapy response biomarker, and even as a therapeutic target. Next-generation RNA sequencing has an unprecedented potential to measure the transcriptome. However, due to the complexity of dealing with isoforms, the scientific community has not sufficiently exploited this valuable resource in precision medicine. FINDINGS: We present TranscriptAchilles, the first large-scale tool to predict transcript biomarkers associated with gene essentiality in cancer. This application integrates 412 loss-of-function RNA interference screens of >17,000 genes, together with their corresponding whole-transcriptome expression profiling. Using this tool, we have studied which are the cancer subtypes for which alternative splicing plays a significant role to state gene essentiality. In addition, we include a case study of renal cell carcinoma that shows the biological soundness of the results. The databases, the source code, and a guide to build the platform within a Docker container are available at GitLab. The application is also available online. CONCLUSIONS: TranscriptAchilles provides a user-friendly web interface to identify transcript or gene biomarkers of gene essentiality, which could be used as a starting point for a drug development project. This approach opens a wide range of translational applications in cancer.
  • Autores: Kim, J. W.; Marquez, C. P.; Kostyrko, K.; et al.
    Revista: NATURE MEDICINE
    ISSN: 1078-8956 Vol.25 N° 11 2019 págs. 1783 - 1795
    Resumen
    Proinflammatory cytokines in the tumor microenvironment can promote tumor growth, yet their value as therapeutic targets remains underexploited. We validated the functional significance of the cardiotrophin-like cytokine factor 1 (CLCF1)-ciliary neurotrophic factor receptor (CNTFR) signaling axis in lung adenocarcinoma (LUAD) and generated a high-affinity soluble receptor (eCNTFR-Fc) that sequesters CLCF1, thereby inhibiting its oncogenic effects. eCNTFR-Fc inhibits tumor growth in multiple xenograft models and in an autochthonous, highly aggressive genetically engineered mouse model of LUAD, driven by activation of oncogenic Kras and loss of Trp53. Abrogation of CLCF1 through eCNTFR-Fc appears most effective in tumors driven by oncogenic KRAS. We observed a correlation between the effectiveness of eCNTFR-Fc and the presence of KRAS mutations that retain the intrinsic capacity to hydrolyze guanosine triphosphate, suggesting that the mechanism of action may be related to altered guanosine triphosphate loading. Overall, we nominate blockade of CLCF1-CNTFR signaling as a novel therapeutic opportunity for LUAD and potentially for other tumor types in which CLCF1 is present in the tumor microenvironment.
  • Autores: Martinez-Terroba, E.; Behrens, C.; Agorreta Arrazubi, Jackeline (Autor de correspondencia); et al.
    Revista: THORAX
    ISSN: 0040-6376 Vol.74 N° 4 2019 págs. 371 - 379
    Resumen
    Introduction Prognostic biomarkers have been very elusive in the lung squamous cell carcinoma (SCC) and none is currently being used in the clinical setting. We aimed to identify and validate the clinical utility of a protein-based prognostic signature to stratify patients with early lung SCC according to their risk of recurrence or death. Methods Patients were staged following the new International Association for the Study of Lung Cancer (IASLC) staging criteria (eighth edition, 2018). Three independent retrospective cohorts of 117, 96 and 105 patients with lung SCC were analysed to develop and validate a prognostic signature based on immunohistochemistry for five proteins. Results We identified a five protein-based signature whose prognostic index (PI) was an independent and significant predictor of disease-free survival (DFS) (p<0.001; HR=4.06, 95% CI 2.18 to 7.56) and overall survival (OS) (p=0.004; HR=2.38, 95% CI 1.32 to 4.31). The prognostic capability of PI was confirmed in an external multi-institutional cohort for DFS (p=0.042; HR=2.01, 95% CI 1.03 to 3.94) and for OS (p=0.031; HR=2.29, 95% CI 1.08 to 4.86). Moreover, PI added complementary information to the newly established IASLC TNM 8th edition staging system. A combined prognostic model including both molecular and anatomical (TNM) criteria improved the risk stratification in both cohorts (p<0.05). Conclusion We have identified and validated a clinically feasible protein-based prognostic model that complements the updated TNM system allowing more accurate risk stratification. This signature may be used as an advantageous tool to improve the clinical management of the patients, allowing the reduction of lung SCC mortality through a more accurate knowledge of the patient's potential outcome.
  • Autores: Giordano, F; Vaira, V; Cortinovis, D; et al.
    Revista: JOURNAL OF EXPERIMENTAL AND CLINICAL CANCER RESEARCH
    ISSN: 1756-9966 Vol.38 N° 1 2019 págs. 260
  • Autores: Expósito Rincón, Francisco; Villalba. M.; Redrado Jordán, Miriam; et al.
    Revista: CANCER LETTERS
    ISSN: 0304-3835 Vol.453 2019 págs. 21 - 33
    Resumen
    High mortality rates caused by NSCLC show the need for the identification of novel therapeutic targets. In this study we have investigated the biological effects and molecular mechanisms elicited by TMPRSS4 in NSCLC. Overexpression of TMPRSS4 in LKR13¿cells increased malignancy, subcutaneous tumor growth and multiorganic metastasis. In conditional knock-down (KD) experiments, abrogation of TMPRSS4 in H358 and H2170¿cells altered proliferation, clonogenicity, tumor engraftment and tumor growth. Reduction in S and G2/M phases of the cell cycle, decreased BrdU incorporation and increased apoptosis was also found. Transcriptomic analysis in KD cells revealed downregulation of genes involved in DNA replication, such as MCM6, TYMS and CDKN1A (p21). In patients, expression of a signature of MCM6/TYMS/TMPRSS4 genes was highly associated with poor prognosis. Downregulation of TMPRSS4 significantly increased sensitivity to chemotherapy agents. In experiments using cisplatin, apoptosis and expression of the DNA-damage marker ¿-H2A was higher in cells lacking TMPRSS4. Moreover, in vivo assays demonstrated that tumors with no TMPRSS4 were significantly more sensitive to cisplatin than controls. These results show that TMPRSS4 can be considered as a novel target in NSCLC, whose inhibition increases chemosensitivity.
  • Autores: Hermida-Prado, F. ; Villaronga, M. A.; Granda-Diaz, R. ; et al.
    Revista: INDIAN JOURNAL OF CLINICAL MEDICINE
    ISSN: 1179-9161 Vol.8 N° 8 2019
    Resumen
    The frequent dysregulation of SRC family kinases (SFK) in multiple cancers prompted various inhibitors to be actively tested in preclinical and clinical trials. Disappointingly, dasatinib and saracatinib failed to demonstrate monotherapeutic efficacy in patients with head and neck squamous cell carcinomas (HNSCC). Deeper functional and mechanistic knowledge of the actions of these drugs is therefore needed to improve clinical outcome and to develop more efficient combinational strategies. Even though the SFK inhibitors dasatinib and saracatinib robustly blocked cell migration and invasion in HNSCC cell lines, this study unveils undesirable stem cell-promoting functions that could explain the lack of clinical efficacy in HNSCC patients. These deleterious effects were targeted by the mithramycin analog EC-8042 that efficiently eliminated cancer stem cells (CSC)-enriched tumorsphere cultures as well as tumor bulk cells and demonstrated potent antitumor activity in vivo. Furthermore, combination treatment of dasatinib with EC-8042 provided favorable complementary anti-proliferative, anti-invasive, and anti-CSC functions without any noticeable adverse interactions of both agents. These findings strongly support combinational strategies with EC-8042 for clinical testing in HNSCC patients. These data may have implications on ongoing dasatinib-based trials.
  • Autores: Castilla Ruíz, Carlos (Autor de correspondencia); Maska, M.; Sorokin, D. V. ; et al.
    Revista: IEEE TRANSACTIONS ON MEDICAL IMAGING
    ISSN: 0278-0062 Vol.38 N° 3 2019 págs. 862 - 872
    Resumen
    We present a 3D bioimage analysis workflow to quantitatively analyze single, actin-stained cells with filopodial protrusions of diverse structural and temporal attributes, such as number, length, thickness, level of branching, and lifetime, in time-lapse confocal microscopy image data. Our workflow makes use of convolutional neural networks trained using real as well as synthetic image data, to segment the cell volumes with highly heterogeneous fluorescence intensity levels and to detect individual filopodial protrusions, followed by a constrained nearest-neighbor tracking algorithm to obtain valuable information about the spatio-temporal evolution of individual filopodia. We validated the workflow using real and synthetic 3-D time-lapse sequences of lung adenocarcinoma cells of three morphologically distinct filopodial phenotypes and show that it achieves reliable segmentation and tracking performance, providing a robust, reproducible and less time-consuming alternative to manual analysis of the 3D+t image data.
  • Autores: Conde, E. ; Hernandez, S.; Martinez, R.; et al.
    Revista: JOURNAL OF THORACIC ONCOLOGY
    ISSN: 1556-0864 Vol.14 N° 12 2019 págs. 2120 - 2132
    Resumen
    Introduction: The ROS1 gene rearrangement has become an important biomarker in NSCLC. The College of American Pathologists/International Association for the Study of Lung Cancer/Association for Molecular Pathology testing guidelines support the use of ROS1 immunohistochemistry (IHC) as a screening test, followed by confirmation with fluorescence in situ hybridization (FISH) or a molecular test in all positive results. We have evaluated a novel anti-ROS1 IHC antibody (SP384) in a large multicenter series to obtain real-world data. Methods: A total of 43 ROS1 FISH-positive and 193 ROS1 FISH-negative NSCLC samples were studied. All specimens were screened by using two antibodies (clone D4D6 from Cell Signaling Technology and clone SP384 from Ventana Medical Systems), and the different interpretation criteria were compared with break-apart FISH (Vysis). FISH-positive samples were also analyzed with next-generation sequencing (Oncomine Dx Target Test Panel, Thermo Fisher Scientific). Results: An H-score of 150 or higher or the presence of at least 70% of tumor cells with an intensity of staining of 2thorn or higher by the SP384 clone was the optimal cutoff value (both with 93% sensitivity and 100% specificity). The D4D6 clone showed similar results, with an H-score of at least 100 (91% sensitivity and 100% specificity). ROS1 expression in normal lung was more frequent with use of the SP384 clone (p < 0.0001). The ezrin gene (EZR)-ROS1 variant was associated with membranous staining and an isolated green signal FISH pattern (p = 0.001 and p = 0.017, respectively). Conclusions: The new SP384 ROS1 IHC clone showed excellent sensitivity without compromising specificity, so it is another excellent analytical option for the proposed testing algorithm. (C) 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
  • Autores: Carazo Melo, Fernando; Gimeno, M.; Ferrer-Bonsoms Hernández, Juan Ángel; et al.
    Revista: BMC GENOMICS
    ISSN: 1471-2164 Vol.20 N° Art. 521 2019
    Resumen
    BackgroundSplicing is a genetic process that has important implications in several diseases including cancer. Deciphering the complex rules of splicing regulation is crucial to understand and treat splicing-related diseases. Splicing factors and other RNA-binding proteins (RBPs) play a key role in the regulation of splicing. The specific binding sites of an RBP can be measured using CLIP experiments. However, to unveil which RBPs regulate a condition, it is necessary to have a priori hypotheses, as a single CLIP experiment targets a single protein.ResultsIn this work, we present a novel methodology to predict context-specific splicing factors from transcriptomic data. For this, we systematically collect, integrate and analyze more than 900 CLIP experiments stored in four CLIP databases: POSTAR2, CLIPdb, DoRiNA and StarBase. The analysis of these experiments shows the strong coherence between the binding sites of RBPs of similar families. Augmenting this information with expression changes, we are able to correctly predict the splicing factors that regulate splicing in two gold-standard experiments in which specific splicing factors are knocked-down.ConclusionsThe methodology presented in this study allows the prediction of active splicing factors in either cancer or any other condition by only using the information of transcript expression. This approach opens a wide range of possible studies to understand the splicing regulation of different conditions. A tutorial with the source code and databases is available at https://gitlab.com/fcarazo.m/sfprediction.
  • Autores: Redin, E. ; Villalba, M. ; Exposito, F.; et al.
    Revista: JOURNAL OF THORACIC ONCOLOGY
    ISSN: 1556-0864 Vol.14 N° 10 2019 págs. S698 - S699
  • Autores: Pérez Gracia, José Luis; Pita, G.; Segura Ruiz, Victor; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN: 0732-183X Vol.37 N° 15 2019
  • Autores: Arjona, D. ; Montuenga, L. M.; Pio Osés, Rubén
    Revista: MOLECULAR IMMUNOLOGY
    ISSN: 0161-5890 Vol.114 2019 págs. 421 - 422
  • Autores: Exposito, F.; Villalba, M. ; Pajares, M. J.; et al.
    Revista: JOURNAL OF THORACIC ONCOLOGY
    ISSN: 1556-0864 Vol.14 N° 10 2019 págs. S501
  • Autores: Pros, E. ; Saigi, M.; Bejar, J. J. A.; et al.
    Revista: JOURNAL OF THORACIC ONCOLOGY
    ISSN: 1556-0864 Vol.14 N° 10 2019 págs. S428 - S428
  • Autores: De Andrea, Carlos Eduardo; Villalba Esparza, María; Expósito Rincón, Francisco; et al.
    Revista: MODERN PATHOLOGY
    ISSN: 0893-3952 Vol.32 N° Supl. 2 2019
  • Autores: Senent, Y.; Ortiz Espinosa, Sergio; Remirez, A.; et al.
    Revista: MOLECULAR IMMUNOLOGY
    ISSN: 0161-5890 Vol.114 2019 págs. 433 - 433
  • Autores: Bosch-Barrera, J. ; Priego, N. ; Puigdemont, M. ; et al.
    Revista: JOURNAL OF THORACIC ONCOLOGY
    ISSN: 1556-0864 Vol.14 N° 10 2019 págs. S658 - S658
  • Autores: Baraibar Argota, Iosune; Roman, M. ; López Erdozain, María Inés; et al.
    Revista: JOURNAL OF THORACIC ONCOLOGY
    ISSN: 1556-0864 Vol.14 N° 10 2019 págs. S320 - S320
  • Autores: Bosch-Barrera, J. ; Hernandez, A.; Priego, N. ; et al.
    Revista: JOURNAL OF THORACIC ONCOLOGY
    ISSN: 1556-0864 Vol.14 N° 10 2019 págs. S1021 - S1022
  • Autores: Martínez Monge, Rafael (Autor de correspondencia); Valtueña Peydro, Germán; Cambeiro Vázquez, Felix Mauricio; et al.
    Revista: BRACHYTHERAPY
    ISSN: 1538-4721 Vol.17 N° 6 2018 págs. 1045
  • Autores: Rodríguez Rodríguez, Javier; Vicent Cambra, Silvestre; Chopitea Ortega, Ana; et al.
    Revista: CLINICAL CANCER RESEARCH
    ISSN: 1078-0432 Vol.24 N° 16 2018 págs. 3787 - 3789
    Resumen
    Although molecular subtype-based stratification and genomic signatures of increasing complexity are becoming a new strategy to guide therapeutic decisions in stage II/III colon cancer, several prognostic factors that can be easily obtained from formalin-fixed paraffin-embedded (FFPE) specimens should be considered to create combined models that better define individual patients' needs. (C) 2018 AACR.
  • Autores: Ajona Martínez-Polo, Daniel; Zandueta Pascual, Carolina; Corrales Pecino, Leticia; et al.
    Revista: AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
    ISSN: 1073-449X Vol.197 N° 9 2018 págs. 1164 - 1176
    Resumen
    RATIONALE: C5aR1 (CD88), a receptor for complement anaphylatoxin C5a, is a potent immune mediator. Its impact on malignant growth and dissemination of non-small cell lung cancer cells is poorly understood. OBJECTIVES: To investigate the contribution of the C5a/C5aR1 axis to the malignant phenotype of non-small cell lung cancer cells, particularly in skeletal colonization, a preferential lung metastasis site. METHODS: Association between C5aR1 expression and clinical outcome was assessed in silico and validated by immunohistochemistry. Functional significance was evaluated by lentiviral gene silencing and ligand l-aptamer inhibition in in vivo models of lung cancer bone metastasis. In vitro functional assays for signaling, migration, invasion, metalloprotease activity, and osteoclastogenesis were also performed. MEASUREMENTS AND MAIN RESULTS: High levels of C5aR1 in human lung tumors were significantly associated with shorter recurrence-free survival, overall survival, and bone metastasis. Silencing of C5aR1 in lung cancer cells led to a substantial reduction in skeletal metastatic burden and osteolysis in in vivo models. Furthermore, metalloproteolytic, migratory, and invasive tumor cell activities were modulated in vitro by C5aR1 stimulation or gene silencing. l-Aptamer blockade or C5aR1 silencing significantly reduced the osseous metastatic activity of lung cancer cells in vivo. This effect was associated with decreased osteoclastogenic activity in vitro and was rescued by the exogenous addition of the chemokine CXCL16. CONCLUSIONS: Disruption of C5aR1 signaling in lung cancer cells abrogates their tumor-associated osteoclastogenic activity, impairing osseous colonization. This study unveils the role played by the C5a/C5aR1 axis in lung cancer dissemination and supports its potential use as a novel therapeutic target.
  • Autores: Jiménez-Fonseca, P. (Autor de correspondencia); Martín, M. N. ; Carmona-Bayonas, A. ; et al.
    Revista: ONCOTARGET
    ISSN: 1949-2553 Vol.9 N° 97 2018 págs. 36894 - 36905
    Resumen
    Several circulating biomarkers and single nucleotide polymorphisms (SNPs) have been correlated with efficacy and tolerability to antiangiogenic agents. These associations remain unexplored in well-differentiated, metastatic pancreatic neuroendocrine tumors treated with the multitargeted tyrosine kinase inhibitor sunitinib. We have assessed the effect on tumor response at 6 months, overall survival, progression-free survival and safety of 14 SNPs, and 6 soluble proteins. Forty-three patients were recruited. Two SNPs in the vascular endothelial growth factor receptor 3 (VEGFR-3) gene predicted lower overall survival: rs307826 with hazard ratio (HR) 3.67 (confidence interval [CI] 95%, 1.35-10.00) and rs307821 with HR 3.84 (CI 95%, 1.47-10.0). Interleukin-6 was associated with increased mortality: HR 1.06 (CI 95%, 1.01-1.12), and osteopontin was associated with shorter PFS: HR 1.087 (1.01-1.16), independently of Ki-67. Furthermore, levels of osteopontin remained higher at the end of the study in patients considered non-responders: 38.5 ng/mL vs. responders: 18.7 ng/mL, p-value=0.039. Dynamic upward variations were also observed with respect to IL-8 levels in sunitinib-refractory individuals: 28.5 pg/mL at baseline vs. 38.3 pg/mL at 3 months, p-value=0.024. In conclusion, two VEGFR-3 SNPs as well as various serum biomarkers were associated with diverse clinical outcomes in patients with well-differentiated pancreatic neuroendocrine tumors treated with sunitinib.
  • Autores: Fusco Morales, Juan Pablo; Pita, G.; Pajares Villandiego, María José; et al.
    Revista: CANCER MEDICINE
    ISSN: 2045-7634 Vol.7 N° 7 2018 págs. 3474 - 3483
    Resumen
    Single nucleotide polymorphisms (SNPs) may modulate individual susceptibility to carcinogens. We designed a genome-wide association study to characterize individuals presenting extreme phenotypes of high and low risk to develop tobacco-induced non-small cell lung cancer (NSCLC), and we validated our results. We hypothesized that this strategy would enrich the frequencies of the alleles that contribute to the observed traits. We genotyped 2.37 million SNPs in 95 extreme phenotype individuals, that is: heavy smokers that either developed NSCLC at an early age (extreme cases); or did not present NSCLC at an advanced age (extreme controls), selected from a discovery set (n=3631). We validated significant SNPs in 133 additional subjects with extreme phenotypes selected from databases including >39,000 individuals. Two SNPs were validated: rs12660420 (p(combined)=5.66x10(-5); ORcombined=2.80), mapping to a noncoding transcript exon of PDE10A; and rs6835978 (p(combined)=1.02x10(-4); ORcombined=2.57), an intronic variant in ATP10D. We assessed the relevance of both proteins in early-stage NSCLC. PDE10A and ATP10D mRNA expressions correlated with survival in 821 stage I-II NSCLC patients (p=0.01 and p<0.0001). PDE10A protein expression correlated with survival in 149 patients with stage I-II NSCLC (p=0.002). In conclusion, we validated two variants associated with extreme phenotypes of high and low risk of developing tobacco-induced NSCLC. Our findings may allow to identify individuals presenting high and low risk to develop tobacco-induced NSCLC and to characterize molecular mechanisms of carcinogenesis and resistance to develop NSCLC.
  • Autores: Catena, R.; Montuenga Badía, Luis; Bodenmiller, B. (Autor de correspondencia)
    Revista: JOURNAL OF PATHOLOGY
    ISSN: 0022-3417 Vol.244 N° 4 2018 págs. 479 - 484
    Resumen
    Imaging mass cytometry is a novel imaging modality that enables simultaneous antibody-based detection of >40 epitopes and molecules in tissue sections at subcellular resolution by the use of isotopically pure metal tags. Essential for any imaging approach in which antigen detection is performed is counterstaining, which reveals the overall structure of the tissue. Counterstaining is necessary because antigens of interest are often present in only a small subset of cells, and the rest of the tissue structures are not visible. As most biological tissues are nearly transparent or non-fluorescent, chromogenic reagents such as haematoxylin (for immunohistochemistry) or fluorescent dyes such as 4,6-diamidino-2-phenylindole (which stains nuclei for epifluorescence and confocal microscopy) are utilized. Here, we describe a metal-based counterstain for imaging mass cytometry based on simple oxidation and subsequent covalent binding of the tissue components to ruthenium tetroxide (RuO4). RuO4 counterstaining reveals general tissue structure both in areas with high cell content and in stromal areas with low cellularity and fibrous or hyaline material in a manner analogous to haematoxylin in immunohistochemical counterstaining or eosin or other anionic dyes in conventional histology. Our new counterstain approach is applicable to any metal-based imaging technique, and will facilitate the adaptation of imaging mass cytometry for routine applications in clinical and research laboratories. Copyright (c) 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
  • Autores: Martinez-Terroba, E.; Behrens, C.; de Miguel, F. J.; et al.
    Revista: JOURNAL OF PATHOLOGY
    ISSN: 0022-3417 Vol.245 N° 4 2018 págs. 421 - 432
    Resumen
    Each of the pathological stages (I-IIIa) of surgically resected non-small-cell lung cancer has hidden biological heterogeneity, manifested as heterogeneous outcomes within each stage. Thus, the finding of robust and precise molecular classifiers with which to assess individual patient risk is an unmet medical need. Here, we identified and validated the clinical utility of a new prognostic signature based on three proteins (BRCA1, QKI, and SLC2A1) to stratify early-stage lung adenocarcinoma patients according to their risk of recurrence or death. Patients were staged according to the new International Association for the Study of Lung Cancer (IASLC) staging criteria (8th edition, 2018). A test cohort (n=239) was used to assess the value of this new prognostic index (PI) based on the three proteins. The prognostic signature was developed by Cox regression with the use of stringent statistical criteria (TRIPOD: Transparent reporting of a multivariable prediction model for individual prognosis or diagnosis). The model resulted in a highly significant predictor of 5-year outcome for disease-free survival (p<0.001) and overall survival (p<0.001). The prognostic ability of the model was externally validated in an independent multi-institutional cohort of patients (n=114, p=0.021). We also demonstrated that this molecular classifier adds relevant information to the gold standard TNM-based pathological staging, with a highly significant improvement of the likelihood ratio. We subsequently developed a combined PI including both the molecular and the pathological data that improved the risk stratification in both cohorts (p <= 0.001). Moreover, the signature may help to select stage I-IIA patients who might benefit from adjuvant chemotherapy. In summary, this protein-based signature accurately identifies those patients with a high risk of recurrence and death, and adds further prognostic information to the TNM-based clinical staging, even when the new IASLC 8th edition staging criteria are applied. More importantly, it may be a valuable tool for selecting patients for adjuvant therapy. Copyright (C) 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
  • Autores: Walle, T.; Martínez Monge, Rafael; Cerwenka, A.; et al.
    Revista: THERAPEUTIC ADVANCES IN MEDICAL ONCOLOGY
    ISSN: 1758-8340 Vol.10 2018
    Resumen
    Radiotherapy (RT) is currently used in more than 50% of cancer patients during the course of their disease in the curative, adjuvant or palliative setting. RT achieves good local control of tumor growth, conferring DNA damage and impacting tumor vasculature and the immune system. Formerly regarded as a merely immunosuppressive treatment, pre- and clinical observations indicate that the therapeutic effect of RT is partially immune mediated. In some instances, RT synergizes with immunotherapy (IT), through different mechanisms promoting an effective antitumor immune response. Cell death induced by RT is thought to be immunogenic and results in modulation of lymphocyte effector function in the tumor microenvironment promoting local control. Moreover, a systemic immune response can be elicited or modulated to exert effects outside the irradiation field (so called abscopal effects). In this review, we discuss the body of evidence related to RT and its immunogenic potential for the future design of novel combination therapies.
  • Autores: Martinez-Terroba, E.; Ezponda Itoiz, Teresa; Bértolo Martín de Rosales, Cristina María; et al.
    Revista: LABORATORY INVESTIGATION
    ISSN: 0023-6837 Vol.98 N° 12 2018 págs. 1562 - 1574
    Resumen
    In recent years, the relevance of RNA metabolism has been increasingly recognized in a variety of diseases. Modifications in the levels of RNA-binding proteins elicit changes in the expression of cancer-related genes. Here we evaluate whether SRSF1 regulates the expression of DNA repair genes, and whether this regulation has a relevant role in lung carcinogenesis. An in silico analysis was performed to evaluate the association between the expression of SRSF1 and DNA repair genes. In vitro functional analyses were conducted in SRSF1 or DNA ligase 1 (LIG1)-downregulated non-small cell lung cancer (NSCLC) cell lines. In addition, the prognostic value of LIG1 was evaluated in NSCLC patients by immunohistochemistry. We found a significant correlation between the DNA repair gene LIG1 and SRSF1 in NSCLC cell lines. Moreover, SRSF1 binds to LIG1 mRNA and regulates its expression by increasing its mRNA stability and enhancing its translation in an mTOR-dependent manner. Furthermore, siRNA-mediated LIG1 inhibition reduced proliferation and increased apoptosis of NSCLC cells. Finally, the expression of LIG1 was an independent prognostic factor for NSCLC, as confirmed in a series of 210 patients. These results show that LIG1 is regulated by the oncoprotein SRSF1 and plays a relevant role in lung cancer cell proliferation and progression. LIG1 is associated with poor prognosis in non-small lung cancer patients.
  • Autores: Bleau, Anne Marie; Redrado Jordán, Miriam; Nistal-Villán, E.; et al.
    Revista: CANCER LETTERS
    ISSN: 1872-7980 Vol.414 2018 págs. 257 - 267
    Resumen
    A major complication of colorectal cancer (CRC), one of the most frequent and deadly types of cancer, is disease progression via liver metastases. At this stage, very few treatment options are available for patients, and the disease remains incurable. Herein, we used a well-established mouse model of CRC liver metastasis (CLM) to identify new regulators of this process. Using serial transplantation of murine MC38 adenocarcinoma cells, we obtained liver metastatic variants that displayed extremely strong colonization abilities. Using these newly established cell lines, we performed gene expression arrays and microRNA (miR) profiling. Comparative and predictive analyses between the two arrays showed higher expression of c-met and concomitant reduction of miR-146a in the mestastatic variants. In CRC patients, expression levels of both c-met and miR-146a were similar between primary tumors and liver metastases. Interestingly, we identified c-met as a new target for miR-146a, as miR-146a was able to impede c-met translation. Of relevance, overexpression of miR-146a in metastatic clones showed reduced in vitro malignancy and abolished the development of primary tumor and liver metastases. Our results document a new mechanism for c-met regulation in CLM and highlight the crucial role of miR-146a in suppressing tumorigenesis.
  • Autores: Romero Riojas, Juan Pablo; Ortiz-Estevez, M.; Muniategui Merino, Ander; et al.
    Revista: BMC GENOMICS
    ISSN: 1471-2164 Vol.19 N° 703 2018
    Resumen
    Background: RNA-seq is a reference technology for determining alternative splicing at genome-wide level. Exon arrays remain widely used for the analysis of gene expression, but show poor validation rate with regard to splicing events. Commercial arrays that include probes within exon junctions have been developed in order to overcome this problem. We compare the performance of RNA-seq (Illumina HiSeq) and junction arrays (Affymetrix Human Transcriptome array) for the analysis of transcript splicing events. Three different breast cancer cell lines were treated with CX-4945, a drug that severely affects splicing. To enable a direct comparison of the two platforms, we adapted EventPointer, an algorithm that detects and labels alternative splicing events using junction arrays, to work also on RNA-seq data. Common results and discrepancies between the technologies were validated and/or resolved by over 200 PCR experiments. Results: As might be expected, RNA-seq appears superior in cases where the technologies disagree and is able to discover novel splicing events beyond the limitations of physical probe-sets. We observe a high degree of coherence between the two technologies, however, with correlation of EventPointer results over 0.90. Through decimation, the detection power of the junction arrays is equivalent to RNA-seq with up to 60 million reads. Conclusions: Our results suggest, therefore, that exon-junction arrays are a viable alternative to RNA-seq for detection of alternative splicing events when focusing on well-described transcriptional regions.
  • Autores: Abou Faycal, C.; Brambilla, E.; Agorreta Arrazubi, Jackeline; et al.
    Revista: BRITISH JOURNAL OF CANCER
    ISSN: 0007-0920 Vol.118 N° 12 2018 págs. 1596 - 1608
    Resumen
    BACKGROUND: While lung adenocarcinoma patients can somewhat benefit from anti-angiogenic therapies, patients with squamous cell lung carcinoma (SQLC) cannot. The reasons for this discrepancy remain largely unknown. Soluble VEGF receptor-1, namely sVEGFR1-i13, is a truncated splice variant of the cell membrane-spanning VEGFR1 that has no transmembrane or tyrosine kinase domain. sVEGFR1-i13 is mainly viewed as an anti-angiogenic factor which counteracts VEGF-A/VEGFR signalling in endothelial cells. However, its role in tumour cells is poorly known. METHODS: mRNA and protein status were analysed by Real-Time qPCR, western blotting, ELISA assay, proximity ligation assay or immunohistochemistry in human tumour cell lines, murine tumourgrafts and non small cell lung carcinoma patients samples. RESULTS: We show that anti-angiogenic therapies specifically increase the levels of sVEGFR1-i13 in SQLC cell lines and chemically induced SQLC murine tumourgrafts. At the molecular level, we characterise a sVEGFR1-i13/beta 1 integrin/VEGFR autocrine loop which determines whether SQLC cells proliferate or go into apoptosis, in response to anti-angiogenic therapies. Furthermore, we show that high levels of both sVEGFR1-i13 and beta 1 integrin mRNAs and proteins are associated with advanced stages in SQLC patients and with a poor clinical outcome in patients with early stage SQLC. CONCLUSIONS: Overall, these results reveal an unexpected pro-tumoural function of sVEGFR1-i13 in SQLC tumour cells, which contributes to their progression and escape from anti-angiogenic therapies. These data might help to understand why some SQLC patients do not respond to anti-angiogenic therapies.
  • Autores: Lozano Escario, María Dolores; Echeveste, José Ignacio; Abengozar Muela, Marta; et al.
    Revista: ARCHIVES OF PATHOLOGY AND LABORATORY MEDICINE
    ISSN: 0003-9985 Vol.142 N° 3 2018 págs. 291 - 298
    Resumen
    CONTEXT: - The rapid advances in targeted therapies in non-small cell lung cancer (NSCLC) make the optimization and implementation of cytology specimens for molecular testing a priority. Up to 70% of patients with NSCLC are diagnosed at advanced stages and tissue biopsies often cannot be taken. Although cytology samples provide high-quality material for molecular testing, molecular cytopathology is not yet well known or widely used. OBJECTIVE: - To report the many advances in molecular cytopathology and the suitability and utility of cytology samples in molecular and genetic testing of NSCLC. DATA SOURCES: - Data sources comprised published peer-reviewed literature and personal experience of the authors. CONCLUSIONS: - Molecular testing can be performed on cytologic specimens, especially on direct smears. Rapid on-site evaluation by cytopathologists has improved the adequacy and the management of cytology samples for molecular testing. Mutational profiling of NSCLC using next-generation sequencing can be performed on cytology samples from very small amounts of DNA. Fluorescence in situ hybridization assays on cytology specimens, including stained direct smear, offer some distinct advantages over their histologic counterpart, and are used to detect ALK and ROS1 rearrangements in NSCLC. Cytology specimens allow assessment of the entire tumor cell nucleus, avoiding signal loss from truncation artifacts. The use of cytology samples for assessing programmed death ligand-1 protein expression is currently being developed. Protocols for bisulfite conversion and DNA droplet digital polymerase chain reaction assays have been optimized for cytology smear to investigate aberrant DNA methylation of several NSCLC-related genes
  • Autores: Quintanal-Villalonga, A.; Ferrer, I. ; Marrugal, A. ; et al.
    Revista: CANCER RESEARCH
    ISSN: 0008-5472 Vol.78 N° 13 Supl. 2018
  • Autores: Banu, A.; Bunting, S. ; Zandueta Pascual, Carolina; et al.
    Revista: JOURNAL OF BONE AND MINERAL RESEARCH
    ISSN: 0884-0431 Vol.33 N° Supl. 1 2018 págs. 46 - 46
  • Autores: Expósito Rincón, Francisco; Villalba, M.; Pajares Villandiego, María José; et al.
    Revista: JOURNAL OF THORACIC ONCOLOGY
    ISSN: 1556-0864 Vol.13 N° 10 2018 págs. S521
  • Autores: Conde, E.; Hernandez, S.; Martinez, R.; et al.
    Revista: JOURNAL OF THORACIC ONCOLOGY
    ISSN: 1556-0864 Vol.13 N° 10 2018 págs. S553 - S554
  • Autores: Gil Bazo, Ignacio; Baraibar Argota, Iosune; Moreno, M. R. ; et al.
    Revista: JOURNAL OF THORACIC ONCOLOGY
    ISSN: 1556-0864 Vol.13 N° 10 2018 págs. S375 - S376
  • Autores: Ajona Martínez-Polo, Daniel; Pajares Villandiego, María José; Freire, J. ; et al.
    Revista: JOURNAL OF THORACIC ONCOLOGY
    ISSN: 1556-0864 Vol.13 N° 10 2018 págs. S394
  • Autores: Conconi, D.; Giordano, F.; Vaira, V. ; et al.
    Revista: EUROPEAN JOURNAL OF CANCER
    ISSN: 0959-8049 Vol.103 N° Supl. 1 2018 págs. E10 - E10
  • Autores: Anguiano Salcedo, María; Morales Urteaga, Xabier; Ariz Galilea, Mikel; et al.
    Revista: CANCER RESEARCH
    ISSN: 0008-5472 Vol.78 N° 13 Supl. 2018 págs. 178 - 178
  • Autores: Patiño García, Ana; Lecanda Cordero, Fernando
    Libro: Bone cancer: bone sarcomas and bone metastases - from bench to bedside
    ISSN: 978-012821666-8 2022 págs. 591 - 604
    Resumen
    Osteosarcoma (OS) is characterized by its complex ontology. Nevertheless, an array of molecular tools for the global analysis at the genomic or postgenomic level has brought to light a wealth of data illuminating some of the molecular intricacies of this tumor. Systematic molecular profiling driven by the emergence of novel technological platforms is shaping our understanding of OS. This review gathers all the information into a comprehensive and systematic summary, underlining the contribution of each gene, protein, or signaling pathway to OS tumorigenesis. We place special emphasis on their functional relevance in chemoresistance and metastasis, together with their potential clinical impact. This chapter should inspire researchers to explore new avenues with potential clinical impact.
  • Autores: Gurpide Ayarra, Luis Alfonso; García del Barrio, María Ángeles; Ortego Zabalza, Ignacio
    Libro: Manual SEOM de cuidados continuos
    ISSN: 978-84-09-15223-0 2019 págs. 135 - 142

Proyectos desde 2018

  • Título: GN 2023 INVESTIGO Pedro Castillo Rosique (COS)
    Código de expediente: 0011-4001-2023-000075
    Investigador principal: PEDRO CASTILLO ROSIQUE.
    Financiador: GOBIERNO DE NAVARRA
    Convocatoria: FIMA 2023 GN Investigo
    Fecha de inicio: 05-10-2023
    Fecha fin: 04-10-2024
    Importe concedido: 33.003,92€
    Otros fondos: Fondos MRR
  • Título: Plataforma para la Identificación de TCR específicos de AntíGenos tumOrales para inmunoteRApia de tumores Sólidos (PITAGORAS)
    Código de expediente: 0011-1411-2023-000072
    Investigador principal: MARIA SANDRA HERVAS STUBBS.
    Financiador: GOBIERNO DE NAVARRA
    Convocatoria: FIMA 2023 GN PROYECTOS ESTRATEGICOS DE I+D 2023-2026
    Fecha de inicio: 01-07-2023
    Fecha fin: 31-12-2025
    Importe concedido: 622.540,20€
    Otros fondos: -
  • Título: Estrategias de mejora de la inmunoterapia antitumoral para cáncer de pulmón y de ovario
    Código de expediente: 0011-4001-2023-000020
    Investigador principal: JOSE ALBERTO FERNANDEZ JUAREZ.
    Financiador: GOBIERNO DE NAVARRA
    Convocatoria: FIMA 2023 GN Investigo
    Fecha de inicio: 20-06-2023
    Fecha fin: 19-06-2024
    Importe concedido: 33.003,92€
    Otros fondos: -
  • Título: Nuevas estrategias terapéuticas para tumores KRAS mutantes
    Código de expediente: 0011-4001-2023-000021
    Investigador principal: JOHANA STHEFANY ALVAREZ JIMENEZ.
    Financiador: GOBIERNO DE NAVARRA
    Convocatoria: FIMA 2023 GN Investigo
    Fecha de inicio: 09-06-2023
    Fecha fin: 14-07-2024
    Importe concedido: 33.003,92€
    Otros fondos: -
  • Título: INtegrative GENomic, digital Imaging and clinical information towars Precision Oncology Optimization ¿ INGENIO
    Código de expediente: PMP21/00107
    Investigador principal: LUIS MONTUENGA BADIA.
    Financiador: INSTITUTO DE SALUD CARLOS III
    Convocatoria: FIMA 2021 Proyectos de I+D+I vinculados a la Medicina Personalizada y Terapias Avanzadas
    Fecha de inicio: 21-03-2023
    Fecha fin: 31-12-2024
    Importe concedido: 153.673,04€
    Otros fondos: Fondos MRR
  • Título: Técnico Investigo 2021 Soporte técnico de actividades investigadoras relacionadas con proyectos de investigación en resistencia a la radioterapia 0011-4001-2022-000072
    Código de expediente: 0011-4001-2022-000072
    Investigador principal: ALFONSO CALVO GONZALEZ.
    Financiador: GOBIERNO DE NAVARRA
    Convocatoria: 2021 GN Investigo
    Fecha de inicio: 09-02-2023
    Fecha fin: 08-02-2024
    Importe concedido: 33.108,92€
    Otros fondos: Fondos MRR
  • Título: Validación de biomarcadores líquidos y de imagen para el diagnóstico de la demencia con cuerpos de Lewy prodrómica
    Código de expediente: PMP22/00100
    Investigador principal: CARLOS ORTIZ DE SOLORZANO AURUSA.
    Financiador: INSTITUTO DE SALUD CARLOS III
    Convocatoria: FIMA 2022 Proyectos de I+D+I vinculados a la Medicina Personalizada y Terapias Avanzadas
    Fecha de inicio: 01-01-2023
    Fecha fin: 31-12-2025
    Importe concedido: 99.000,00€
    Otros fondos: Fondos MRR
  • Título: Reversión de la resistencia a inmunoterapia en cáncer de pulmón debida a ausencia del gen supresor tumoral PTEN
    Código de expediente: GN2022/50
    Investigador principal: ALFONSO CALVO GONZALEZ.
    Financiador: GOBIERNO DE NAVARRA. DEPARTAMENTO DE SALUD
    Convocatoria: 2022 GN Proyectos de Investigación en salud
    Fecha de inicio: 23-12-2022
    Fecha fin: 22-12-2025
    Importe concedido: 76.934,16€
    Otros fondos: -
  • Título: Diagnóstico no invasivo de pacientes con cáncer mediante inteligencia artificial aplicada al análisis de células tumorales circulantes en sangre (DeepCTC)
    Código de expediente: TED2021-131300B-I00
    Investigador principal: CARLOS ORTIZ DE SOLORZANO AURUSA, MIKEL HERNAEZ ARRAZOLA.
    Financiador: MINISTERIO DE CIENCIA E INNOVACIÓN
    Convocatoria: FIMA 2021 MCIU TRANSICION ECOLOGICA Y DIGITAL
    Fecha de inicio: 01-12-2022
    Fecha fin: 30-11-2024
    Importe concedido: 187.450,00€
    Otros fondos: Fondos MRR
  • Título: GNI INVESTIGO 2022 Javier García Chamorro (C.O.S)
    Código de expediente: 0011-4001-2022-000081
    Investigador principal: CARLOS ORTIZ DE SOLORZANO AURUSA, JAVIER GARCIA CHAMORRO.
    Financiador: GOBIERNO DE NAVARRA
    Convocatoria: FIMA 2021 GN Investigo
    Fecha de inicio: 01-12-2022
    Fecha fin: 30-11-2023
    Importe concedido: 33.108,92€
    Otros fondos: Fondos FEDER
  • Título: Análisis cuantitativo de organoides derivados de pacientes de alto valor fisiológico: caracterización in vitro, in situ e in vivo de su morfología y fenotipo
    Código de expediente: PID2021-122409OB-C22
    Investigador principal: CARLOS ORTIZ DE SOLORZANO AURUSA, IVAN CORTES DOMINGUEZ.
    Financiador: MINISTERIO DE CIENCIA E INNOVACIÓN
    Convocatoria: FIMA 2021 MCIU AEI GENERACION CONOCIMIENTO
    Fecha de inicio: 01-09-2022
    Fecha fin: 31-08-2025
    Importe concedido: 145.200,00€
    Otros fondos: -
  • Título: MECANISMOS DE METÁSTASIS EN EL CÁNCER DE PULMÓN
    Código de expediente: PID2021-122638OB-I00
    Investigador principal: FERNANDO LECANDA CORDERO.
    Financiador: MINISTERIO DE CIENCIA E INNOVACIÓN
    Convocatoria: FIMA 2021 MCIU AEI GENERACION CONOCIMIENTO
    Fecha de inicio: 01-09-2022
    Fecha fin: 31-08-2025
    Importe concedido: 248.050,00€
    Otros fondos: -
  • Título: Desarrollo de un test para el diagnóstico precoz no invasivo de cáncer de pulmón basado en marcadores moleculares, imágenes y herramientas de Big DataoncoLung Dx
    Código de expediente: CPP2021-008336
    Investigador principal: RUBEN PIO OSES.
    Financiador: MINISTERIO DE CIENCIA E INNOVACIÓN
    Convocatoria: FIMA 2021 MCI - AEI PROYECTOS DE COLABORACIÓN PUBLICO-PRIVADAS
    Fecha de inicio: 01-06-2022
    Fecha fin: 31-05-2025
    Importe concedido: 188.044,00€
    Otros fondos: Fondos MRR
  • Título: GRANATE - GRUPO DE RADIOTERAPIA AVANZADA DE NAVARRA ¿ TERAPIA Y EFICACIA
    Código de expediente: 0011-1411-2022-000073
    Investigador principal: RUBEN PIO OSES.
    Financiador: GOBIERNO DE NAVARRA
    Convocatoria: FIMA 2022 GN PROYECTOS ESTRATEGICOS DE I+D 2022-2025
    Fecha de inicio: 01-06-2022
    Fecha fin: 31-12-2024
    Importe concedido: 732.063,61€
    Otros fondos: -
  • Título: GRANATE - GRUPO DE RADIOTERAPIA AVANZADA DE NAVARRA ¿ TERAPIA Y EFICACIA
    Código de expediente: 0011-1411-2022-000066
    Investigador principal: ANA PATIÑO GARCIA.
    Financiador: GOBIERNO DE NAVARRA
    Convocatoria: 2022 GN PROYECTOS ESTRATEGICOS DE I+D 2022-2025
    Fecha de inicio: 01-06-2022
    Fecha fin: 31-12-2024
    Importe concedido: 536.739,00€
    Otros fondos: -
  • Título: Adquisición de un equipo de imagen óptica IVIS Spectrum 22
    Código de expediente: 0011-1508-2022-000046
    Investigador principal: CARLOS ORTIZ DE SOLORZANO AURUSA.
    Financiador: GOBIERNO DE NAVARRA
    Convocatoria: FIMA 2022 - GN INDUSTRIA EQUIPOS E INFRAESTRUCTURAS
    Fecha de inicio: 01-03-2022
    Fecha fin: 31-12-2022
    Importe concedido: 181.745,62€
    Otros fondos: -
  • Título: Desarrollo y validación de herramientas microfluídicas airwayon-a-chip para el modelado de la formación de biofilm bacteriano en las vías respiratorias bajas.
    Código de expediente: FPU20/06252
    Investigador principal: CARLOS SOBEJANO DE LA MERCED.
    Financiador: MINISTERIO DE CIENCIA E INNOVACIÓN
    Convocatoria: FIMA 2020 - MINECO BECAS FPU
    Fecha de inicio: 09-12-2021
    Fecha fin: 08-12-2025
    Importe concedido: 90.478,47€
    Otros fondos: -
  • Título: MYCOMBIO. USO DE LA INHIBICIÓN DE MYC PARA SUPERAR LA RESISTENCIA A LA INMUNOTERAPIA EN NSCLC IMPULSADO POR KRAS CON DIVERSOS PERFILES MUTACIONALES
    Código de expediente: PLEC2021-007959
    Investigador principal: SILVESTRE VICENT CAMBRA.
    Financiador: MINISTERIO DE CIENCIA E INNOVACIÓN
    Convocatoria: FIMA 2021 MCI - AEI PROYECTOS DE I+D+I EN LINEAS ESTRATEGICAS FIMA 2021 MCI - AEI PROYECTOS DE I+D+I EN LINEAS ESTRATEGICAS
    Fecha de inicio: 01-12-2021
    Fecha fin: 30-11-2024
    Importe concedido: 277.624,13€
    Otros fondos: Fondos MRR
  • Título: POLIFARMA-3D Hacia la personalización del tratamiento de infecciones respiratorias crónicas polimicrobianas: evaluación de fármacos sostenibles mediante modelos pulmonares 3D
    Código de expediente: 0011-1383-2022-000014
    Investigador principal: CARLOS ORTIZ DE SOLORZANO AURUSA, CARLOS ORTIZ DE SOLORZANO AURUSA.
    Financiador: GOBIERNO DE NAVARRA
    Convocatoria: FIMA 2022 - GN INDUSTRIA PROYECTOS CENTROS TECNOLOGICOS Y ORGANISMOS DE INVESTIGACION.
    Fecha de inicio: 01-12-2021
    Fecha fin: 30-11-2024
    Importe concedido: 231.552,51€
    Otros fondos: -
  • Título: FPU 2020 DANIEL ORIVE L.M
    Código de expediente: FPU20/06292
    Investigador principal: DANIEL ORIVE MAULEON.
    Financiador: MINISTERIO DE CIENCIA E INNOVACIÓN
    Convocatoria: FIMA 2020 - MINECO BECAS FPU
    Fecha de inicio: 17-11-2021
    Fecha fin: 20-09-2025
    Importe concedido: 86.991,20€
    Otros fondos: Fondos FEDER
  • Título: Efectos inmunosupresores de las trampas extracelulares de neutrofilos en cáncer
    Código de expediente: PID2020-113174RA-100
    Investigador principal: ALVARO TEIJEIRA SANCHEZ.
    Financiador: MINISTERIO DE CIENCIA E INNOVACIÓN
    Convocatoria: FIMA 2020 MCIU - AEI PROYECTOS DE I+D RETOS INVESTIGACION
    Fecha de inicio: 01-09-2021
    Fecha fin: 31-08-2024
    Importe concedido: 192.390,00€
    Otros fondos: -
  • Título: Integrating 4-1BB (CD137) agonists, interleukin-12, interleukin-18 and TGFb; antagonists in synergistic combined cancer
    Código de expediente: PID2020-112892RB-100
    Investigador principal: IGNACIO JAVIER MELERO BERMEJO.
    Financiador: MINISTERIO DE CIENCIA E INNOVACIÓN
    Convocatoria: FIMA 2020 MCIU - AEI PROYECTOS DE I+D RETOS INVESTIGACION
    Fecha de inicio: 01-09-2021
    Fecha fin: 31-08-2024
    Importe concedido: 459.800,00€
    Otros fondos: -
  • Título: Estrategias de inhibición para el tratamiento del cáncer de pulmón dirigido por KRAS: de las aproximaciones genéticas a las farmacológicas
    Código de expediente: PID2020-116344RB-I00
    Investigador principal: SILVESTRE VICENT CAMBRA.
    Financiador: MINISTERIO DE CIENCIA E INNOVACIÓN
    Convocatoria: FIMA 2020 MCIU - AEI PROYECTOS DE I+D RETOS INVESTIGACION
    Fecha de inicio: 01-09-2021
    Fecha fin: 31-08-2024
    Importe concedido: 235.950,00€
    Otros fondos: -
  • Título: Aplicaciones del estudio multi-ómico de la microbiota al desarrollo de soluciones biotecnológicas innovadoras en el área de la salud (microBiomics)
    Código de expediente: 0011-1411-2021-000106
    Investigador principal: MARIA TERESA HERRAIZ BAYOD, MARIA TERESA HERRAIZ BAYOD.
    Financiador: GOBIERNO DE NAVARRA
    Convocatoria: 2021 GN PROYECTOS ESTRATEGICOS DE I+D 2021-2024
    Fecha de inicio: 15-04-2021
    Fecha fin: 31-12-2023
    Importe concedido: 366.577,17€
    Otros fondos: -
  • Título: 2^2-INTRATARGET: nanomedicinas para la liberación de administrar anticuerpos
    Código de expediente: AC20/00117
    Investigador principal: ALFONSO CALVO GONZALEZ.
    Financiador: INSTITUTO DE SALUD CARLOS III
    Convocatoria: 2020 AES Programación Conjunta Internacional
    Fecha de inicio: 01-01-2021
    Fecha fin: 31-12-2023
    Importe concedido: 174.998,67€
    Otros fondos: -
  • Título: 3D3B-AVATAR
    Código de expediente: 0011-1411-2020-000047
    Investigador principal: CARLOS ORTIZ DE SOLORZANO AURUSA.
    Financiador: GOBIERNO DE NAVARRA
    Convocatoria: FIMA 2020 GN PROYECTOS ESTRATEGICOS DE I+D 2020-2022
    Fecha de inicio: 01-08-2020
    Fecha fin: 30-11-2022
    Importe concedido: 289.683,32€
    Otros fondos: -
  • Título: Alianza en Genómica Avanzada para el desarrollo de Terapias Personalizadas en Navarra
    Código de expediente: 0011-1411-2020-000010
    Investigador principal: FELIPE LUIS PROSPER CARDOSO.
    Financiador: GOBIERNO DE NAVARRA
    Convocatoria: FIMA 2020 GN PROYECTOS ESTRATEGICOS DE I+D 2020-2022
    Fecha de inicio: 17-06-2020
    Fecha fin: 30-11-2022
    Importe concedido: 725.480,08€
    Otros fondos: -
  • Título: Nuevas combinaciones inmunomoduladoras frente al adenocarcinoma de pulmón según el estado mutacional del oncogen KRAS. Estudio de nuevos biomarcadores de respuesta a terapia anti-PD-1
    Código de expediente: PI19/00678
    Investigador principal: IGNACIO GIL BAZO.
    Financiador: INSTITUTO DE SALUD CARLOS III
    Convocatoria: 2019 AES Proyectos de investigación
    Fecha de inicio: 01-01-2020
    Fecha fin: 31-12-2022
    Importe concedido: 111.320,00€
    Otros fondos: Fondos FEDER
  • Título: Evaluación de YES1 como nueva diana terapéutica y biomarcador de respuesta a dasanitib en cáncer de pulmón.
    Código de expediente: PI19/00230
    Investigador principal: ALFONSO CALVO GONZALEZ.
    Financiador: INSTITUTO DE SALUD CARLOS III
    Convocatoria: 2019 AES Proyectos de investigación
    Fecha de inicio: 01-01-2020
    Fecha fin: 31-12-2022
    Importe concedido: 127.050,00€
    Otros fondos: Fondos FEDER
  • Título: Desarrollo nanotecnológico de antimicrobianos innovadores y su evaluación farmacológica mediante dispositivos microfluídicos "airway on a chip"
    Código de expediente: 0011-1383-2020-000013
    Investigador principal: CARLOS ORTIZ DE SOLORZANO AURUSA.
    Financiador: GOBIERNO DE NAVARRA
    Convocatoria: FIMA 2020 - GN INDUSTRIA PROYECTOS CENTROS TECNOLOGICOS Y ORGANISMOS DE INVESTIGACION
    Fecha de inicio: 01-12-2019
    Fecha fin: 30-11-2022
    Importe concedido: 243.357,63€
    Otros fondos: -
  • Título: Desarrollo de un sistema microfluídico para el aislamiento y enriquecimiento de células tumorales circulantes (CTCs) en biopsia líquida
    Código de expediente: 0011-1383-2020-000013
    Investigador principal: IVAN CORTES DOMINGUEZ.
    Financiador: GOBIERNO DE NAVARRA
    Convocatoria: FIMA 2020 - GN INDUSTRIA PROYECTOS CENTROS TECNOLOGICOS Y ORGANISMOS DE INVESTIGACION
    Fecha de inicio: 01-12-2019
    Fecha fin: 30-11-2022
    Importe concedido: 206.092,36€
    Otros fondos: -
  • Título: FPU 2018 YAIZA SENENT RP
    Código de expediente: FPU18/02638
    Investigador principal: YAIZA SENENT VALERO.
    Financiador: MINISTERIO DE CIENCIA E INNOVACIÓN
    Convocatoria: 2018 - MINECO BECAS FPU
    Fecha de inicio: 01-10-2019
    Fecha fin: 30-09-2023
    Importe concedido: 83.227,68€
    Otros fondos: Fondos FSE
  • Título: BECAS FPU MOVILIDAD 2018 SERGIO ORTIZ RP
    Código de expediente: EST18/00130
    Investigador principal: SERGIO ORTIZ ESPINOSA.
    Financiador: MINISTERIO DE CIENCIA E INNOVACIÓN
    Convocatoria: 2018 - FIMA MINECO BECAS FPU MOVILIDAD
    Fecha de inicio: 01-06-2019
    Fecha fin: 31-08-2019
    Importe concedido: 3.900,00€
    Otros fondos: -
  • Título: JOSE CASTILLEJO 2018 IVAN CORTES
    Código de expediente: CAS18/00444
    Investigador principal: IVAN CORTES DOMINGUEZ.
    Financiador: MINISTERIO DE CIENCIA E INNOVACIÓN
    Convocatoria: 2018 - MINECO ESTANCIAS JOSE CASTILLEJO
    Fecha de inicio: 01-03-2019
    Fecha fin: 31-08-2019
    Importe concedido: 17.046,00€
    Otros fondos: -
  • Título: FJCI-2017-34233 OIHANE ERICE SV
    Código de expediente: FJCI-2017-34233
    Investigador principal: SILVESTRE VICENT CAMBRA.
    Financiador: MINISTERIO DE CIENCIA E INNOVACIÓN
    Convocatoria: 2017 - MINECO CONTRATOS JUAN DE LA CIERVA FORMACION 2017 - MINECO CONTRATOS JUAN DE LA CIERVA FORMACION
    Fecha de inicio: 01-01-2019
    Fecha fin: 28-07-2021
    Importe concedido: 54.178,08€
    Otros fondos: Fondos FEDER
  • Título: Microfluidics, mechanobiology and image analysis for the simulation of tumoral growth in 3D (TUMOUR-ON-A-CHIP)
    Código de expediente: RTI2018-094494-B-C22
    Investigador principal: CARLOS ORTIZ DE SOLORZANO AURUSA, IVAN CORTES DOMINGUEZ.
    Financiador: MINISTERIO DE CIENCIA E INNOVACIÓN
    Convocatoria: 2018 - PROYECTOS DE I+D RETOS INVESTIGACION
    Fecha de inicio: 01-01-2019
    Fecha fin: 30-09-2022
    Importe concedido: 129.470,00€
    Otros fondos: Fondos FEDER
  • Título: MECHANISMS OF METASTASIS IN LUNG CANCER (MECMET)
    Código de expediente: RTI2018-094507-B-I00
    Investigador principal: FERNANDO LECANDA CORDERO.
    Financiador: MINISTERIO DE CIENCIA E INNOVACIÓN
    Convocatoria: 2018 - PROYECTOS DE I+D RETOS INVESTIGACION
    Fecha de inicio: 01-01-2019
    Fecha fin: 30-09-2022
    Importe concedido: 181.500,00€
    Otros fondos: Fondos FEDER
  • Título: IED3 SILVESTRE VICENT
    Código de expediente: IED2019-001007-I
    Investigador principal: SILVESTRE VICENT CAMBRA.
    Financiador: MINISTERIO DE CIENCIA E INNOVACIÓN
    Convocatoria: FIMA 2019 MINECO I3
    Fecha de inicio: 01-01-2019
    Fecha fin: 31-12-2021
    Importe concedido: 100.000,00€
    Otros fondos: Fondos FEDER
  • Título: Descifrando el papel clínico-funcional del entramado transcripcional de FOSL1-FRA1 en el colangiocarcinoma hepático (DesciFRA)
    Código de expediente: 58/2018
    Investigador principal: SILVESTRE VICENT CAMBRA.
    Financiador: GOBIERNO DE NAVARRA. DEPARTAMENTO DE SALUD
    Convocatoria: 2018 PROYECTOS DE I+D EN SALUD
    Fecha de inicio: 31-12-2018
    Fecha fin: 30-12-2021
    Importe concedido: 79.563,90€
    Otros fondos: Fondos FEDER
  • Título: Desarrollo de un sistema de aislamiento y enriquecimiento de células tumorales circulantes en sangre mediante dispositivos microfluídicos.
    Código de expediente: 0011-1383-2019-000006
    Investigador principal: CARLOS ORTIZ DE SOLORZANO AURUSA.
    Financiador: GOBIERNO DE NAVARRA
    Convocatoria: 2019 - GN INDUSTRIA PROYECTOS CENTROS TECNOLOGICOS Y ORGANISMOS DE INVESTIGACION
    Fecha de inicio: 01-12-2018
    Fecha fin: 30-11-2019
    Importe concedido: 75.296,51€
    Otros fondos: -
  • Título: Desarrollo y validación de un sistema hiperespectral para análisis de biopsias de tejidos sólidos. QUASAR
    Código de expediente: RTC-2017-6218-1
    Investigador principal: CARLOS ORTIZ DE SOLORZANO AURUSA.
    Financiador: MINISTERIO DE CIENCIA E INNOVACIÓN
    Convocatoria: 2017 - PROYECTOS RETOS-COLABORACION
    Fecha de inicio: 01-10-2018
    Fecha fin: 30-09-2022
    Importe concedido: 178.588,00€
    Otros fondos: Fondos FEDER
  • Título: Potenciación de la inmunoterapia frente al cáncer de pulmón mediante la modulación del microambiente tumoral
    Código de expediente: FPU17/00032
    Investigador principal: SERGIO ORTIZ ESPINOSA.
    Financiador: MINISTERIO DE CIENCIA E INNOVACIÓN
    Convocatoria: 2017 - MINECO BECAS FPU 2017 - MINECO BECAS FPU
    Fecha de inicio: 06-09-2018
    Fecha fin: 21-01-2021
    Importe concedido: 51.858,36€
    Otros fondos: Fondos FEDER
  • Título: Solicitud Juan de la Cierva Incorporación, tutor Alfonso Calvo
    Código de expediente: IJCI-2016-27595
    Investigador principal: ALFONSO CALVO GONZALEZ.
    Financiador: MINISTERIO DE CIENCIA E INNOVACIÓN
    Convocatoria: 2016 MINECO JUAN DE LA CIERVA INCORPORACION
    Fecha de inicio: 01-09-2018
    Fecha fin: 31-12-2020
    Importe concedido: 64.000,00€
    Otros fondos: Fondos FEDER
  • Título: Desarrollo de tecnologías microfluídicas y ópticas para la generación y visualización 3D de organoides tumorales en matrices biomiméticas. (TUMORVIEW3D)
    Código de expediente: 0011-1365-2018-000089
    Investigador principal: CARLOS ORTIZ DE SOLORZANO AURUSA.
    Financiador: GOBIERNO DE NAVARRA
    Convocatoria: 2018 GN I+D
    Fecha de inicio: 01-03-2018
    Fecha fin: 30-04-2020
    Importe concedido: 142.643,56€
    Otros fondos: -
  • Título: Desarrollo de un sistema de aislamiento y enriquecimiento de células tumorales circulantes en sangre mediante dispositivos microfluídicos
    Código de expediente: 0011-1383-2018-000011
    Investigador principal: CARLOS ORTIZ DE SOLORZANO AURUSA.
    Financiador: GOBIERNO DE NAVARRA
    Convocatoria: 2018 - GN INDUSTRIA PROYECTOS CENTROS TECNOLOGICOS Y ORGANISMOS DE INVESTIGACION
    Fecha de inicio: 01-02-2018
    Fecha fin: 30-11-2018
    Importe concedido: 70.481,10€
    Otros fondos: -
  • Título: Nueva estrategia terapéutica para evitar el escape inmune en cáncer de pulmón metastásico mediante el bloqueo combinado de PD-1 e Id1
    Código de expediente: 74/2017
    Investigador principal: IGNACIO GIL BAZO.
    Financiador: GOBIERNO DE NAVARRA
    Convocatoria: 2017 GN SALUD
    Fecha de inicio: 01-01-2018
    Fecha fin: 15-12-2020
    Importe concedido: 90.000,00€
    Otros fondos: Fondos FEDER
  • Título: Potenciación de la inmunoterapia frente al cáncer de pulmón mediante la modulación de la respuesta tumoral innata
    Código de expediente: PI17/00411
    Investigador principal: RUBEN PIO OSES, DANIEL AJONA MARTINEZ - POLO.
    Financiador: INSTITUTO DE SALUD CARLOS III
    Convocatoria: 2017 - PROYECTOS DE I+D EN SALUD
    Fecha de inicio: 01-01-2018
    Fecha fin: 31-12-2020
    Importe concedido: 123.420,00€
    Otros fondos: Fondos FEDER
  • Título: Regulación de mecanismos celulares autónomos y no autónomos por nuevas interacciones sintético-letales con KRAS: implicación funcional, molecular y clínica en cáncer de pulmón
    Código de expediente: SAF2017-89944-R
    Investigador principal: SILVESTRE VICENT CAMBRA.
    Financiador: MINISTERIO DE CIENCIA E INNOVACIÓN
    Convocatoria: 2017 MINECO RETOS
    Fecha de inicio: 01-01-2018
    Fecha fin: 31-12-2020
    Importe concedido: 169.400,00€
    Otros fondos: Fondos FEDER
  • Título: IDP4SCLC Optimización de fármacos en nuevas dianas terapéuticas IDP (ASCL1) para el tratamiento de cáncer microcítico de pulmón
    Código de expediente: RTC-2017-6585-1
    Investigador principal: FERNANDO LECANDA CORDERO.
    Financiador: MINISTERIO DE CIENCIA E INNOVACIÓN
    Convocatoria: 2017 - PROYECTOS RETOS-COLABORACION
    Fecha de inicio: 01-01-2018
    Fecha fin: 31-12-2020
    Importe concedido: 134.923,52€
    Otros fondos: Fondos FEDER
  • Título: Caracterización de la recíproca interacción oncogén/ remodeladores de cromatina en tumorogénesis y metástasis en el cáncer de pulmón
    Código de expediente: 77/2017
    Investigador principal: FERNANDO LECANDA CORDERO.
    Financiador: GOBIERNO DE NAVARRA. DEPARTAMENTO DE SALUD
    Convocatoria: 2017 PROYECTOS DE I+D EN SALUD
    Fecha de inicio: 15-12-2017
    Fecha fin: 15-09-2021
    Importe concedido: 64.842,75€
    Otros fondos: Fondos FEDER
  • Título: NANO-IMMUNOTHERAPY: INTRACELLULAR TARGETING OF CANCER CELLS AND TAMS
    Código de expediente: PCIN-2017-017
    Investigador principal: IVAN PEÑUELAS SANCHEZ.
    Financiador: MINISTERIO DE CIENCIA E INNOVACIÓN
    Convocatoria: 2017 MINECO APCIN
    Fecha de inicio: 01-10-2017
    Fecha fin: 30-06-2021
    Importe concedido: 100.000,00€
    Otros fondos: -
  • Título: DIANA: Tecnología de secuenciación de nueva generación (NGS) para optimizar la eficacia del diagnóstico y tratamiento en pacientes con tumores de alta mortalidad (Diagnostico biomédico e Innovación Abierta en Navarra)
    Código de expediente: 0011-1411-2017-000029
    Investigador principal: RUBEN PIO OSES.
    Financiador: GOBIERNO DE NAVARRA
    Convocatoria: 2017 - GN INDUSTRIA PROYECTOS ESTRATEGICOS
    Fecha de inicio: 01-04-2017
    Fecha fin: 30-11-2019
    Importe concedido: 730.651,96€
    Otros fondos: -
  • Título: Análisis molecular mediante plataformas de última generación del carcinoma no microcítico de pulmón para el desarrollo de perfiles pronósticos y nuevas herramientas terapéuticas
    Código de expediente: PI16/01821
    Investigador principal: LUIS MONTUENGA BADIA.
    Financiador: INSTITUTO DE SALUD CARLOS III
    Convocatoria: 2016 - PROYECTOS DE I+D EN SALUD
    Fecha de inicio: 01-01-2017
    Fecha fin: 31-12-2019
    Importe concedido: 128.865,00€
    Otros fondos: Fondos FEDER
  • Título: TMPRSS4: un nuevo biomarcador y diana terapéutica en carcinoma escamoso de pulmón de mal pronóstico
    Código de expediente: PI16/01352
    Investigador principal: ALFONSO CALVO GONZALEZ.
    Financiador: INSTITUTO DE SALUD CARLOS III
    Convocatoria: 2016 AES PROYECTOS DE INVESTIGACIÓN
    Fecha de inicio: 01-01-2017
    Fecha fin: 31-12-2019
    Importe concedido: 98.615,00€
    Otros fondos: Fondos FEDER
  • Título: Desarrollo y prototipado de sistemas de seguimiento celular para el análisis de cultivos tridimensionales organotípicos en plataformas microfluídicas. (ORGANSCREEN)
    Código de expediente: 0011-1365-2016-000301
    Investigador principal: CARLOS ORTIZ DE SOLORZANO AURUSA.
    Financiador: GOBIERNO DE NAVARRA
    Convocatoria: 2016 - GN PROYECTOS TRACTORES DE CENTROS TECNOLOGICOS (ADITECH)
    Fecha de inicio: 01-07-2016
    Fecha fin: 31-08-2018
    Importe concedido: 141.019,30€
    Otros fondos: -
  • Título: Contrato Predoctoral Gobierno Vasco Convocatoria 2015 Irati Garmendia
    Código de expediente:
    Investigador principal: IRATI GARMENDIA ITURBE.
    Financiador: GOBIERNO VASCO
    Convocatoria: 2015 - GV PREDOCTORAL 2015 - GV PREDOCTORAL
    Fecha de inicio: 01-02-2016
    Fecha fin: 31-01-2019
    Importe concedido: 59.101,78€
    Otros fondos: -
  • Título: MECANISMOS DE METÁSTASIS EN MODELOS AUTÓCTONOS DE CÁNCER DE PULMÓN
    Código de expediente: SAF2015-71606-R
    Investigador principal: FERNANDO LECANDA CORDERO.
    Financiador: MINISTERIO DE CIENCIA E INNOVACIÓN
    Convocatoria: 2015 - PROYECTOS DE I+D RETOS
    Fecha de inicio: 01-01-2016
    Fecha fin: 31-12-2018
    Importe concedido: 151.840,00€
    Otros fondos: Fondos FEDER
  • Título: Técnicas de adquisición y análisis de imagen microscópica para la cuantificación de la extravasación tumoral en dispositivos microfluídicos
    Código de expediente: DPI2015-64221-C2-2-R
    Investigador principal: CARLOS ORTIZ DE SOLORZANO AURUSA.
    Financiador: MINISTERIO DE CIENCIA E INNOVACIÓN
    Convocatoria: 2015 - PROYECTOS DE I+D RETOS
    Fecha de inicio: 01-01-2016
    Fecha fin: 30-06-2019
    Importe concedido: 82.577,60€
    Otros fondos: Fondos FEDER
  • Título: Desarrollo de una plataforma completa para el análisis de células sanguíneas con alta sensibilidad y especificidad. platform cell.
    Código de expediente: RTC-2015-4167-1
    Investigador principal: CARLOS ORTIZ DE SOLORZANO AURUSA.
    Financiador: MINISTERIO DE CIENCIA E INNOVACIÓN
    Convocatoria: 2014 - PROYECTOS RETOS-COLABORACION
    Fecha de inicio: 01-09-2015
    Fecha fin: 30-04-2018
    Importe concedido: 143.904,00€
    Otros fondos: Fondos FEDER
  • Título: Aproximación de alto rendimiento a la cuantificación por imagen de la migración celular en microdispositivos microfluídicos
    Código de expediente: BES-2013-064996
    Investigador principal: CARLOS ORTIZ DE SOLORZANO AURUSA.
    Financiador: MINISTERIO DE CIENCIA E INNOVACIÓN
    Convocatoria: 2013 - MINECO FPI
    Fecha de inicio: 01-10-2014
    Fecha fin: 30-09-2018
    Importe concedido: 83.900,00€
    Otros fondos: Fondos FEDER
  • Título: Development of novel strategies to fight locoregional recurrence in lung cancer based on the discovery of radiosensibilizing therapies
    Código de expediente:
    Investigador principal: DIEGO SERRANO TEJERO
    Financiador: LUNG CANCER RESEARCH FOUNDATION
    Convocatoria: ILCF Research Grants 2022
    Fecha de inicio: 01-09-2022
    Fecha fin: 31-08-2023
    Importe concedido: 50.000,00€
    Otros fondos: -
  • Título: Dual Serine/ Threonine and Tyrosine kinase (DSTYK) as a new target for lung cancer therapy and immunotherapy combination
    Código de expediente: KLV 111219
    Investigador principal: LUIS MONTUENGA BADIA
    Financiador: International Association for the Study of Lung Cancer (IASLC)
    Convocatoria: International Lung Cancer Foundation Fellowship and Young Investigator Awards
    Fecha de inicio: 01-07-2020
    Fecha fin: 30-06-2021
    Importe concedido: 42.500,00€
    Otros fondos: -
  • Título: KRASmiRNA: Dissecting the functional role of KRAS-driven miRNAs in Lung Cancer
    Código de expediente: 16-0224
    Investigador principal: SILVESTRE VICENT CAMBRA
    Financiador: WORLDWIDE CANCER RESEARCH (WCR)
    Convocatoria: WCR ABRIL 2015
    Fecha de inicio: 15-01-2016
    Fecha fin: 30-09-2019
    Importe concedido: 187.596,90€
    Otros fondos: -
  • Título: AECC INVES234938VALE
    Investigador principal: KARMELE VALENCIA LEOZ
    Financiador: ASOCIACION ESPAÑOLA CONTRA EL CANCER
    Convocatoria: FIMA 2023 Investigador AECC
    Fecha de inicio: 01-07-2023
    Fecha fin: 30-06-2026
    Importe concedido: 150.000,00€
  • Título: Short-term starvation to improve the antitumor activity and attenuate the side effects of lung cancer immunotherapy
    Investigador principal: DANIEL AJONA MARTINEZ - POLO
    Financiador: ASOCIACION ESPAÑOLA CONTRA EL CANCER
    Convocatoria: FIMA Ideas Semilla AECC 2021
    Fecha de inicio: 01-12-2021
    Fecha fin: 05-01-2024
    Importe concedido: 20.000,00€
  • Título: Nuevos biomarcadores para la determinación personalizada del riesgo de cáncer de pulmón en protocolos de cribado por TAC de baja dosis: desarrollo y validación de firmas proteicas de alta sensibilidad en combinación con análisis radiómico.
    Investigador principal: LUIS MONTUENGA BADIA
    Financiador: ASTRA ZENECA FARMACEUTICA SPAIN, S.A.
    Convocatoria: FIMA LUNG AMBITION ALLIANCE, FIMA LUNG AMBITION ALLIANCE, FIMA LUNG AMBITION ALLIANCE, FIMA LUNG AMBITION ALLIANCE
    Fecha de inicio: 27-10-2021
    Fecha fin: 26-10-2024
    Importe concedido: 153.333,00€
  • Título: Rational gene signature-based drug combinations for lung cancer treatment
    Investigador principal: SILVESTRE VICENT CAMBRA, SILVESTRE VICENT CAMBRA
    Financiador: ASOCIACION ESPAÑOLA CONTRA EL CANCER
    Convocatoria: FIMA 2020 Estratégicos AECC
    Fecha de inicio: 01-11-2020
    Fecha fin: 30-04-2024
    Importe concedido: 300.000,00€
  • Título: Combinatorial Immunotherapies in a novel GEMM platform for sarcomas: Identification of Therapeutic Efficacy and anticipating Adverse Events
    Investigador principal: FERNANDO LECANDA CORDERO
    Financiador: ASOCIACION ESPAÑOLA CONTRA EL CANCER
    Convocatoria: FIMA 2020 Estratégicos AECC
    Fecha de inicio: 01-11-2020
    Fecha fin: 29-02-2024
    Importe concedido: 300.000,00€
  • Título: Organ - specific biomarkers and therapies to improve the managemente of brain mestastasis
    Investigador principal: ALFONSO CALVO GONZALEZ, ALFONSO CALVO GONZALEZ
    Financiador: FUNDACIO "LA MARATO DE TV3"
    Convocatoria: 2019 FD LA MARATÓ PROYECTOS DE INVESTIGACIÓN
    Fecha de inicio: 22-09-2020
    Fecha fin: 31-01-2024
    Importe concedido: 125.000,00€
  • Título: Overcoming immunotherapeutic resistance through Myc inhibition in KRas-driven NSCLC with diverse mutational landscape
    Investigador principal: SILVESTRE VICENT CAMBRA
    Financiador: FUNDACIO "LA MARATO DE TV3"
    Convocatoria: FIMA 2019 FD LA MARATÓ TV3 PROYECTOS DE INVESTIGACIÓN
    Fecha de inicio: 13-07-2020
    Fecha fin: 12-07-2023
    Importe concedido: 109.687,50€
  • Título: Terapia personalizada para Cáncer de Pulmón con distinto paisaje mutacional mediante cultivos 3D de organoides
    Investigador principal: SILVESTRE VICENT CAMBRA
    Financiador: FUNDACION BBVA
    Convocatoria: Becas Leonardo 2018
    Fecha de inicio: 30-09-2018
    Fecha fin: 29-03-2020
    Importe concedido: 40.000,00€
  • Título: Potenciación antitumoral y antimetastásica mediante la modulación del sistema de complemento
    Investigador principal: RUBEN PIO OSES
    Financiador: ASOCIACION ESPAÑOLA CONTRA EL CANCER
    Convocatoria: Proyectos AECC 2017
    Fecha de inicio: 01-12-2017
    Fecha fin: 31-03-2021
    Importe concedido: 300.000,00€
  • Título: Uso de estrategias moleculares de última generación para la identificación de nuevas dianas terapéuticas y marcadores pronósticos en tipos de carcinoma pulmonar pobremente caracterizados
    Investigador principal: LUIS MONTUENGA BADIA
    Financiador: ASOCIACION ESPAÑOLA CONTRA EL CANCER
    Convocatoria: 2014 PROYECTOS DE INVESTIGACIÓN GRUPOS ESTABLES
    Fecha de inicio: 01-11-2017
    Fecha fin: 31-10-2020
    Importe concedido: 192.000,00€
  • Título: Nueva estrategia terapéutica para evitar el escape inmune en cáncer de pulmón metastásico mediante el bloqueo combinado PD-1 e Id1
    Investigador principal: IGNACIO GIL BAZO
    Financiador: FUNDACION MERCK SALUD
    Convocatoria: 2016 MERCK SALUD
    Fecha de inicio: 01-06-2017
    Fecha fin: 06-06-2020
    Importe concedido: 30.000,00€
  • Título: The c-MET pathway activation status, pro-angiogenic chemokin
    Investigador principal: ALFONSO CALVO GONZALEZ
    Fecha de inicio: 17-03-2015
    Fecha fin: 30-03-2020
    Importe: 0
    Otros fondos: -
  • Título: Determinación de factores analizados en muestras tumorales
    Investigador principal: ALFONSO CALVO GONZALEZ
    Fecha de inicio: 13-03-2015
    Fecha fin: 30-11-2019
    Importe: 0
    Otros fondos: -