Fat1 deletion promotes hybrid EMT state, tumour stemness and metastasis
Ievgenia Pastushenko 1 2 3 , Federico Mauri 1 , Yura Song 1 , Florian de Cock 1 , Bob Meeusen 4 5 , Benjamin Swedlund 1 , Francis Impens 6 7 8 , Delphi Van Haver 6 7 8 , Matthieu Opitz 9 , Manuel Thery 10 11 , Yacine Bareche 12 , Gaelle Lapouge 1 , Marjorie Vermeersch 13 , Yves-Rémi Van Eycke 14 15 , Cédric Balsat 14 , Christine Decaestecker 14 15 , Youri Sokolow 16 , Sergio Hassid 17 , Alicia Perez-Bustillo 18 , Beatriz Agreda-Moreno 19 , Luis Rios-Buceta 20 21 22 , Pedro Jaen 20 21 22 , Pedro Redondo 23 , Ramon Sieira-Gil 24 , Jose F Millan-Cayetano 25 , Onofre Sanmatrtin 26 , Nicky D'Haene 27 , Virginie Moers 1 , Milena Rozzi 1 , Jeremy Blondeau 1 , Sophie Lemaire 1 , Samuel Scozzaro 1 , Veerle Janssens 4 5 , Magdalena De Troya 25 , Christine Dubois 1 , David Pérez-Morga 13 28 , Isabelle Salmon 27 , Christos Sotiriou 12 , Francoise Helmbacher 29 , Cédric Blanpain 30 31
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.
CITA DEL ARTÍCULO Nature. 2020 Dec 16. doi: 10.1038/s41586-020-03046-1