RT Journal Article
T1 Fat1 deletion promotes hybrid EMT state, tumour stemness and metastasis.
A1 Pastushenko, Ievgenia
A1 Mauri, Federico
A1 Song, Yura
A1 de Cock, Florian
A1 Meeusen, Bob
A1 Swedlund, Benjamin
A1 Impens, Francis
A1 Van Haver, Delphi
A1 Opitz, Matthieu
A1 Thery, Manuel
A1 Bareche, Yacine
A1 Lapouge, Gaelle
A1 Vermeersch, Marjorie
A1 Van Eycke, Yves-Rémi
A1 Balsat, Cédric
A1 Decaestecker, Christine
A1 Sokolow, Youri
A1 Hassid, Sergio
A1 Perez-Bustillo, Alicia
A1 Agreda-Moreno, Beatriz
A1 Rios-Buceta, Luis
A1 Jaen, Pedro
A1 Redondo, Pedro
A1 Sieira-Gil, Ramon
A1 Millan-Cayetano, Jose F
A1 Sanmatrtin, Onofre
A1 D'Haene, Nicky
A1 Moers, Virginie
A1 Rozzi, Milena
A1 Blondeau, Jeremy
A1 Lemaire, Sophie
A1 Scozzaro, Samuel
A1 Janssens, Veerle
A1 De Troya, Magdalena
A1 Dubois, Christine
A1 Pérez-Morga, David
A1 Salmon, Isabelle
A1 Sotiriou, Christos
A1 Helmbacher, Francoise
A1 Blanpain, Cédric
AB 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 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 accelerates 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 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, promoting SOX2 expression, 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.
YR 2020
FD 2020-12-16
LK https://hdl.handle.net/10668/26673
UL https://hdl.handle.net/10668/26673
LA en
DS RISalud
RD Apr 8, 2025