Fat1 deletion promotes hybrid EMT state, tumour stemness and metastasis

Ievgenia Pastushenko, Federico Mauri, Yura Song, Florian Cock, Bob Meeusen, Benjamin Swedlund, Francis Impens, Delphi Haver, Matthieu Opitz, Manuel Thery, Yacine Bareche, Gaelle Lapouge, Marjorie Vermeersch, Yves-Rémi Eycke, Cédric Balsat, Christine Decaestecker, Youri Sokolow, Sergio Hassid, Alicia Perez-Bustillo, Beatriz Agreda-Moreno, Luis Rios-Buceta, Pedro Jaen, Pedro Redondo, Ramon Sieira-Gil, Jose F. Millan-Cayetano, Onofre Sanmatrtin, Nicky D’Haene, Virginie Moers, Milena Rozzi, Jeremy Blondeau, Sophie Lemaire, Samuel Scozzaro, Veerle Janssens, Magdalena Troya, Christine Dubois, David Pérez-Morga, Isabelle Salmon, Christos Sotiriou, Francoise Helmbacher and Cédric Blanpain ()
Additional contact information
Ievgenia Pastushenko: Université Libre de Bruxelles (ULB)
Federico Mauri: Université Libre de Bruxelles (ULB)
Yura Song: Université Libre de Bruxelles (ULB)
Florian Cock: Université Libre de Bruxelles (ULB)
Bob Meeusen: KU Leuven
Benjamin Swedlund: Université Libre de Bruxelles (ULB)
Francis Impens: VIB Center for Medical Biotechnology
Delphi Haver: VIB Center for Medical Biotechnology
Matthieu Opitz: Alvéole
Manuel Thery: CytoMorpho Lab, UMR976 HIPI, CEA, INSERM, Université de Paris
Yacine Bareche: Breast Cancer Translational Research Laboratory J.-C. Heuson, Institut Jules Bordet, Université Libre de Bruxelles (ULB)
Gaelle Lapouge: Université Libre de Bruxelles (ULB)
Marjorie Vermeersch: Center for Microscopy and Molecular Imaging (CMMI), Université Libre de Bruxelles (ULB)
Yves-Rémi Eycke: DIAPath, Center for Microscopy and Molecular Imaging, Université Libre de Bruxelles (ULB)
Cédric Balsat: DIAPath, Center for Microscopy and Molecular Imaging, Université Libre de Bruxelles (ULB)
Christine Decaestecker: DIAPath, Center for Microscopy and Molecular Imaging, Université Libre de Bruxelles (ULB)
Youri Sokolow: Erasme University Hospital, Université Libre de Bruxelles (ULB)
Sergio Hassid: Erasme University Hospital, Université Libre de Bruxelles (ULB)
Alicia Perez-Bustillo: Complejo Asistencial Universitario de León
Beatriz Agreda-Moreno: Hospital Clinico ‘Lozano Blesa’
Luis Rios-Buceta: Ramón y Cajal Hospital
Pedro Jaen: Ramón y Cajal Hospital
Pedro Redondo: Clinica Universidad de Navarra
Ramon Sieira-Gil: Head and Neck Surgery, Hospital Clínic
Jose F. Millan-Cayetano: Hospital Costa del Sol
Onofre Sanmatrtin: Instituto Valenciano de Oncologia
Nicky D’Haene: Université Libre de Bruxelles (ULB)
Virginie Moers: Université Libre de Bruxelles (ULB)
Milena Rozzi: Université Libre de Bruxelles (ULB)
Jeremy Blondeau: Université Libre de Bruxelles (ULB)
Sophie Lemaire: Université Libre de Bruxelles (ULB)
Samuel Scozzaro: Université Libre de Bruxelles (ULB)
Veerle Janssens: KU Leuven
Magdalena Troya: Hospital Costa del Sol
Christine Dubois: Université Libre de Bruxelles (ULB)
David Pérez-Morga: Center for Microscopy and Molecular Imaging (CMMI), Université Libre de Bruxelles (ULB)
Isabelle Salmon: Université Libre de Bruxelles (ULB)
Christos Sotiriou: Breast Cancer Translational Research Laboratory J.-C. Heuson, Institut Jules Bordet, Université Libre de Bruxelles (ULB)
Francoise Helmbacher: Aix-Marseille Univ, CNRS, IBDM - UMR
Cédric Blanpain: Université Libre de Bruxelles (ULB)

Nature, 2021, vol. 589, issue 7842, 448-455

Abstract: 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.

Date: 2021
References: Add references at CitEc
Citations: View citations in EconPapers (8)

Downloads: (external link)
https://www.nature.com/articles/s41586-020-03046-1 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:589:y:2021:i:7842:d:10.1038_s41586-020-03046-1

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-020-03046-1

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().