Fat1deletion promotes hybrid EMT state, tumour stemness and metastasis

Autor: Pastushenko, Ievgenia, Mauri, Federico, Song, Yura, de Cock, Florian, Meeusen, Bob, Swedlund, Benjamin, Impens, Francis, Van Haver, Delphi, Opitz, Matthieu, Thery, Manuel, Bareche, Yacine, Lapouge, Gaelle, Vermeersch, Marjorie, Van Eycke, Yves-Rémi, Balsat, Cédric, Decaestecker, Christine, Sokolow, Youri, Hassid, Sergio, Perez-Bustillo, Alicia, Agreda-Moreno, Beatriz, Rios-Buceta, Luis, Jaen, Pedro, Redondo, Pedro, Sieira-Gil, Ramon, Millan-Cayetano, Jose F., Sanmatrtin, Onofre, D’Haene, Nicky, Moers, Virginie, Rozzi, Milena, Blondeau, Jeremy, Lemaire, Sophie, Scozzaro, Samuel, Janssens, Veerle, De Troya, Magdalena, Dubois, Christine, Pérez-Morga, David, Salmon, Isabelle, Sotiriou, Christos, Helmbacher, Francoise, Blanpain, Cédric
Zdroj: Nature; January 2021, Vol. 589 Issue: 7842 p448-455, 8p
Abstrakt: FAT1, which encodes a protocadherin, is one of the most frequently mutated genes in human cancers1–5. However, the role and the molecular mechanisms by which FAT1mutations 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 Fat1accelerates tumour 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 Fat1was 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 FAT1activates a CAMK2–CD44–SRC axis that promotes YAP1 nuclear translocation and ZEB1expression that stimulates the mesenchymal state. This loss of function also inactivates EZH2, promoting SOX2expression, 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 FAT1promotes tumour initiation, progression, invasiveness, stemness and metastasis through the induction of a hybrid EMT state.
Databáze: Supplemental Index
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