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Fat1 deletion promotes hybrid EMT state, tumour stemness and metastasis

Author

Listed:
  • Ievgenia Pastushenko

    (Université Libre de Bruxelles (ULB)
    Cliniques de l’Europe
    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
    Leuven Cancer Institute (LKI))

  • Benjamin Swedlund

    (Université Libre de Bruxelles (ULB))

  • Francis Impens

    (VIB Center for Medical Biotechnology
    VIB Proteomics Core
    Ghent University)

  • Delphi Haver

    (VIB Center for Medical Biotechnology
    VIB Proteomics Core
    Ghent University)

  • Matthieu Opitz

    (Alvéole)

  • Manuel Thery

    (CytoMorpho Lab, UMR976 HIPI, CEA, INSERM, Université de Paris
    CytoMorpho Lab, UMR5168 LPCV, CEA, CNRS, Université Grenoble-Alpes)

  • 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)
    Laboratory of Image Synthesis and Analysis, Ecole Polytechnique de Bruxelles, 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)
    Laboratory of Image Synthesis and Analysis, Ecole Polytechnique de Bruxelles, 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
    University of Alcalá
    Instituto Ramón y Cajal de Investigación Sanitaria (IRyCIS))

  • Pedro Jaen

    (Ramón y Cajal Hospital
    University of Alcalá
    Instituto Ramón y Cajal de Investigación Sanitaria (IRyCIS))

  • 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
    Leuven Cancer Institute (LKI))

  • 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)
    IBMM, 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)
    WELBIO, Université Libre de Bruxelles (ULB))

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.

Suggested Citation

  • Ievgenia Pastushenko & Federico Mauri & Yura Song & Florian Cock & Bob Meeusen & Benjamin Swedlund & Francis Impens & Delphi Haver & Matthieu Opitz & Manuel Thery & Yacine Bareche & Gaelle Lapouge & M, 2021. "Fat1 deletion promotes hybrid EMT state, tumour stemness and metastasis," Nature, Nature, vol. 589(7842), pages 448-455, January.
    • Handle: RePEc:nat:nature:v:589:y:2021:i:7842:d:10.1038_s41586-020-03046-1
    DOI: 10.1038/s41586-020-03046-1
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    Citations

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    Cited by:

    1. Jiawen Bu & Yixiao Zhang & Sijin Wu & Haonan Li & Lisha Sun & Yang Liu & Xudong Zhu & Xinbo Qiao & Qingtian Ma & Chao Liu & Nan Niu & Jinqi Xue & Guanglei Chen & Yongliang Yang & Caigang Liu, 2023. "KK-LC-1 as a therapeutic target to eliminate ALDH+ stem cells in triple negative breast cancer," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    2. Peter Bailey & Rachel A. Ridgway & Patrizia Cammareri & Mairi Treanor-Taylor & Ulla-Maja Bailey & Christina Schoenherr & Max Bone & Daniel Schreyer & Karin Purdie & Jason Thomson & William Rickaby & R, 2023. "Driver gene combinations dictate cutaneous squamous cell carcinoma disease continuum progression," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    3. Weili Wang & Huizhen Zheng & Jun Jiang & Zhi Li & Dongpeng Jiang & Xiangru Shi & Hui Wang & Jie Jiang & Qianqian Xie & Meng Gao & Jianhong Chu & Xiaoming Cai & Tian Xia & Ruibin Li, 2022. "Engineering micro oxygen factories to slow tumour progression via hyperoxic microenvironments," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    4. Sibo Zhao & Jia Li & Huiyuan Zhang & Lin Qi & Yuchen Du & Mari Kogiso & Frank K. Braun & Sophie Xiao & Yulun Huang & Jianfang Li & Wan-Yee Teo & Holly Lindsay & Patricia Baxter & Jack M. F. Su & Adeku, 2022. "Epigenetic Alterations of Repeated Relapses in Patient-matched Childhood Ependymomas," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    5. Nastaran Mohammadi Ghahhari & Magdalena K. Sznurkowska & Nicolas Hulo & Lilia Bernasconi & Nicola Aceto & Didier Picard, 2022. "Cooperative interaction between ERα and the EMT-inducer ZEB1 reprograms breast cancer cells for bone metastasis," Nature Communications, Nature, vol. 13(1), pages 1-19, December.

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