Publicaciones científicas

Fat1 deletion promotes hybrid EMT state, tumour stemness and metastasis

16-dic-2020 | Revista: Nature

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


Abstract

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

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