Revistas
Revista:
CELLS
ISSN:
2073-4409
Año:
2023
Vol.:
12
N°:
3
Págs.:
374
Glioblastoma (GB) is the most prevalent primary brain cancer and the most aggressive form of glioma because of its poor prognosis and high recurrence. To confirm the importance of epigenetics in glioma, we explored The Cancer Gene Atlas (TCGA) database and we found that several histone/DNA modifications and chromatin remodeling factors were affected at transcriptional and genetic levels in GB compared to lower-grade gliomas. We associated these alterations in our own cohort of study with a significant reduction in the bulk levels of acetylated lysines 9 and 14 of histone H3 in high-grade compared to low-grade tumors. Within GB, we performed an RNA-seq analysis between samples exhibiting the lowest and highest levels of acetylated H3 in the cohort; these results are in general concordance with the transcriptional changes obtained after histone deacetylase (HDAC) inhibition of GB-derived cultures that affected relevant genes in glioma biology and treatment (e.g., A2ML1, CD83, SLC17A7, TNFSF18). Overall, we identified a transcriptional signature linked to histone acetylation that was potentially associated with good prognosis, i.e., high overall survival and low rate of somatic mutations in epigenetically related genes in GB. Our study identifies lysine acetylation as a key defective histone modification in adult high-grade glioma, and offers novel insights regarding the use of HDAC inhibitors in therapy.
Revista:
CANCER CELL
ISSN:
1535-6108
Año:
2023
Vol.:
41
N°:
11
Págs.:
1911-1926
Diffuse intrinsic pontine glioma (DIPG) is an aggressive brain stem tumor and the leading cause of pediatric cancer-related death. To date, these tumors remain incurable, underscoring the need for efficacious therapies. In this study, we demonstrate that the immune checkpoint TIM-3 (HAVCR2) is highly expressed in both tumor cells and microenvironmental cells, mainly microglia and macrophages, in DIPG. We show that inhibition of TIM-3 in syngeneic models of DIPG prolongs survival and produces long-term survivors free of disease that harbor immune memory. This antitumor effect is driven by the direct effect of TIM-3 inhibition in tumor cells, the coordinated action of several immune cell populations, and the secretion of chemokines/cytokines that create a proinflammatory tumor microenvironment favoring a potent antitumor immune response. This work uncovers TIM-3 as a bona fide target in DIPG and supports its clinical translation.
Otros (PIUNA, fundaciones, contratos…)
Título:
Combinatorial biotherapies for the treatment of pediatric diffuse midline glioma
Código de expediente:
PRYGN21937ALON
Investigador principal:
Marta María Alonso Roldán
Financiador:
ASOCIACION ESPAÑOLA CONTRA EL CANCER
Convocatoria:
2021 AECC Proyectos Generales
Fecha de inicio:
01/12/2021
Fecha fin:
30/11/2024
Importe concedido:
300.000,00€
Título:
Terapias avanzadas para tumores sólidos pediátricos
Financiador:
FUNDACIÓN ADEY
Convocatoria:
2021 FD ADEY Proyectos
Fecha de inicio:
01/04/2021
Fecha fin:
31/12/2026
Importe concedido:
120.000,00€