Detalle Publicación

Fat1 deletion promotes hybrid EMT, tumour stemness and metastasis

Autores: Pastushenko, I.; Mauri, F.; Song, Y.; De Cock, F.; Meeusen, B.; Swedlund, B.; Impens, F.; Van Haver, D.; Opitz, M.; Thery, M.; Bareche, Y.; Lapouge, G.; Vermeersch, M.; Van Eycke, Y. R.; Balsat, C.; Decaestecker, C.; Sokolow, Y.; Hassid, S.; Peérez Bustillo, A.; Agrada Moreno, B.; Ríos Buceta, L.; Jaén, P.; Redondo Bellón, Pedro; Sieira Gil, R.; Millán Cayetano, J. F.; San Martín, O.; D'Haene, N.; Moers, V.; Rozzi, M.; Blondeau, J.; Lemaire, S.; Scozzaro, S.; Janssens, V.; De Troya, M.; Dubois, C.; Pérez Morga, D.; Salmon, I.; Sotiriou, C.; Helmbacher, F.; Blanpain, C. (Autor de correspondencia)
Título de la revista: NATURE
ISSN: 0028-0836
Volumen: 589
Páginas: 488 - 455
Fecha de publicación: 2021
FAT1, which encodes a protocadherin, is one ofthe most frequently mutated genes in human cancers(1-5). However, the role and the molecular mechanisms by which FAT1 mutations control tumour initiation and progression are poorly understood. Here, using mouse models of skin squamous cell carcinoma and lung tumours, we found that deletion of Fat1 acceleratestumour initiation and malignant progression and promotes a hybrid epithelial-to-mesenchymal transition (EMT) phenotype. We also found this hybrid EMT state in FAT1-mutated human squamous cell carcinomas. Skin squamous cell carcinomas in which Fat1 was deleted presented increased tumour stemness and spontaneous metastasis. We performed transcriptional and chromatin profiling combined with proteomic analyses and mechanistic studies, which revealed that loss of function of FAT1 activates a CAMK2-CD44-SRC axis that promotes YAP1 nuclear translocation and ZEB1 expression that stimulates the mesenchymal state. This loss of function also inactivates EZH2, promotingSOX2expression, which sustains the epithelial state. Our comprehensive analysis identified drug resistance and vulnerabilities in FAT1-deficient tumours, which have important implications for cancer therapy. Our studies reveal that, in mouse and human squamous cell carcinoma, loss of function of FAT1 promotes tumour initiation, progression, invasiveness, stemness and metastasis through the induction of a hybrid EMT state.