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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, 9 Matthieu Opitz 10 Manuel Thery 11, 12 Yacine Bareche 13 Gaelle Lapouge 1 Marjorie Vermeersch 14 Yves-Rémi van Eycke 15, 16 Cédric Balsat 15 Christine Decaestecker 15, 16 Youri Sokolow 17 Sergio Hassid 18 Alicia Perez-Bustillo 19 Beatriz Agreda-Moreno 20 Luis Rios-Buceta 21, 22, 23 Pedro Jaen 21, 22, 23 Pedro Redondo 24 Ramon Sieira-Gil 25 Jose Millan-Cayetano 26 Onofre Sanmatrtin 27 Nicky D’haene 28 Virginie Moers 1 Milena Rozzi 1 Jeremy Blondeau 1 Sophie Lemaire 1 Samuel Scozzaro 1 Veerle Janssens 4, 5 Magdalena de Troya 26 Christine Dubois 1 David Pérez-Morga 14 Isabelle Salmon 28 Christos Sotiriou 29 Françoise Helmbacher 30 Cédric Blanpain 1, 31
12 CytoMorphoLab
LPCV - Physiologie cellulaire et végétale
Abstract : FAT1, which encodes a protocadherin, is one of the most frequently mutated genes in human cancers. 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.
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https://hal.archives-ouvertes.fr/hal-03081403
Contributor : Francoise Helmbacher Connect in order to contact the contributor
Submitted on : Monday, November 15, 2021 - 6:40:35 PM
Last modification on : Friday, May 6, 2022 - 2:54:41 PM
Long-term archiving on: : Wednesday, February 16, 2022 - 9:18:26 PM

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Ievgenia Pastushenko, Federico Mauri, Yura Song, Florian de Cock, Bob Meeusen, et al.. Fat1 deletion promotes hybrid EMT state, tumour stemness and metastasis. Nature, Nature Publishing Group, 2021, 589 (7842), pp.448-455. ⟨10.1038/s41586-020-03046-1⟩. ⟨hal-03081403⟩

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