Fat1 deletion promotes hybrid EMT state, tumour stemness and metastasis
Ievgenia Pastushenko
(1, 2, 1)
,
Federico Mauri
(1)
,
Yura Song
(1)
,
Florian de Cock
(1)
,
Bob Meeusen
(3, 4)
,
Benjamin Swedlund
(1)
,
Francis Impens
(5, 6, 7)
,
Delphi van Haver
(5, 8)
,
Matthieu Opitz
(9)
,
Manuel Thery
(10, 10, 11)
,
Yacine Bareche
(1)
,
Gaelle Lapouge
(1)
,
Marjorie Vermeersch
(1)
,
Yves-Rémi van Eycke
(1, 12)
,
Cédric Balsat
(1)
,
Christine Decaestecker
(1, 12)
,
Youri Sokolow
(1)
,
Sergio Hassid
(1)
,
Alicia Perez-Bustillo
(13)
,
Beatriz Agreda-Moreno
(14)
,
Luis Rios-Buceta
(15, 16, 17)
,
Pedro Jaen
(15, 16, 17)
,
Pedro Redondo
(18)
,
Ramon Sieira-Gil
(19)
,
Jose Millan-Cayetano
(20)
,
Onofre Sanmatrtin
(21)
,
Nicky D’haene
(1)
,
Virginie Moers
(1)
,
Milena Rozzi
(1)
,
Jeremy Blondeau
(1)
,
Sophie Lemaire
(1)
,
Samuel Scozzaro
(1)
,
Veerle Janssens
(3, 4)
,
Magdalena de Troya
(20)
,
Christine Dubois
(1)
,
David Pérez-Morga
(1)
,
Isabelle Salmon
(1)
,
Christos Sotiriou
(1)
,
Françoise Helmbacher
(22)
,
Cédric Blanpain
(1, 1)
1
ULB -
Université libre de Bruxelles
2 Dermatology Department, Cliniques de l'Europe, Brussels, Belgium
3 KU Leuven - Catholic University of Leuven = Katholieke Universiteit Leuven
4 Leuven Cancer Institute (LKI), Leuven, Belgium
5 VIB-UGent Center for Medical Biotechnology
6 VIB Proteomics Core, Ghent, Belgium
7 UGENT - Universiteit Gent = Ghent University
8 VIB proteomic core, Ghent, Belgium
9 Alvéole, Paris, France.
10 CytoMorphoLab
11 HIPI (UMR_S_976 / U976) - Immunologie humaine, physiopathologie & immunothérapie
12 Ecole Polytechnique de Bruxelles
13 Department of Dermatology, Complejo Asistencial Universitario de León, León, Spain
14 Department of Otolaryngology - Head and Neck Surgery, Hospital Clinico 'Lozano Blesa', Zaragoza, Spain
15 Dermatology Department, Ramón y Cajal Hospital, Madrid, Spain
16 University of Alcalá, Madrid, Spain
17 IRYCIS - Instituto Ramon y Cajal de Investigacion Sanitaria [Madrid, Spain]
18 Department of Dermatology, Clinica Universidad de Navarra, Navarra, Spain
19 Department of Maxillofacial Surgery, Head and Neck Surgery, Hospital Clínic, Barcelona, Spain
20 Department of Dermatology, Hospital Costa del Sol, Marbella, Spain
21 Department of Dermatology, Instituto Valenciano de Oncologia, Valencia, Spain
22 IBDM - Institut de Biologie du Développement de Marseille
2 Dermatology Department, Cliniques de l'Europe, Brussels, Belgium
3 KU Leuven - Catholic University of Leuven = Katholieke Universiteit Leuven
4 Leuven Cancer Institute (LKI), Leuven, Belgium
5 VIB-UGent Center for Medical Biotechnology
6 VIB Proteomics Core, Ghent, Belgium
7 UGENT - Universiteit Gent = Ghent University
8 VIB proteomic core, Ghent, Belgium
9 Alvéole, Paris, France.
10 CytoMorphoLab
11 HIPI (UMR_S_976 / U976) - Immunologie humaine, physiopathologie & immunothérapie
12 Ecole Polytechnique de Bruxelles
13 Department of Dermatology, Complejo Asistencial Universitario de León, León, Spain
14 Department of Otolaryngology - Head and Neck Surgery, Hospital Clinico 'Lozano Blesa', Zaragoza, Spain
15 Dermatology Department, Ramón y Cajal Hospital, Madrid, Spain
16 University of Alcalá, Madrid, Spain
17 IRYCIS - Instituto Ramon y Cajal de Investigacion Sanitaria [Madrid, Spain]
18 Department of Dermatology, Clinica Universidad de Navarra, Navarra, Spain
19 Department of Maxillofacial Surgery, Head and Neck Surgery, Hospital Clínic, Barcelona, Spain
20 Department of Dermatology, Hospital Costa del Sol, Marbella, Spain
21 Department of Dermatology, Instituto Valenciano de Oncologia, Valencia, Spain
22 IBDM - Institut de Biologie du Développement de Marseille
Francis Impens
- Fonction : Auteur
- PersonId : 769098
- ORCID : 0000-0003-2886-9616
Yacine Bareche
- Fonction : Auteur
- PersonId : 792153
- ORCID : 0000-0002-7208-6494
Yves-Rémi van Eycke
- Fonction : Auteur
Christos Sotiriou
- Fonction : Auteur
- PersonId : 762547
- ORCID : 0000-0002-5745-9977
Françoise Helmbacher
- Fonction : Auteur
- PersonId : 19949
- IdHAL : francoise-helmbacher
- ORCID : 0000-0001-6822-1246
- IdRef : 158868862
Résumé
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.
Origine : Fichiers produits par l'(les) auteur(s)