Fat1 deletion promotes hybrid EMT state, tumour stemness and metastasis

Nature. 2021 Jan;589(7842):448-455. doi: 10.1038/s41586-020-03046-1. Epub 2020 Dec 16.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Cadherins / deficiency*
  • Cadherins / genetics
  • Cadherins / metabolism
  • Carcinoma, Squamous Cell / genetics
  • Carcinoma, Squamous Cell / pathology
  • Disease Progression
  • Enhancer of Zeste Homolog 2 Protein / metabolism
  • Epithelial Cells / metabolism
  • Epithelial Cells / pathology
  • Epithelial-Mesenchymal Transition / drug effects
  • Epithelial-Mesenchymal Transition / genetics*
  • Gene Deletion*
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Hyaluronan Receptors / metabolism
  • Lung Neoplasms / genetics
  • Lung Neoplasms / pathology
  • Mesoderm / metabolism
  • Mesoderm / pathology
  • Mice
  • Neoplasm Metastasis / drug therapy
  • Neoplasm Metastasis / genetics*
  • Neoplasms / drug therapy
  • Neoplasms / genetics*
  • Neoplasms / pathology*
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology
  • Phenotype
  • Phosphoproteins / analysis
  • Phosphoproteins / metabolism
  • Proteomics
  • SOXB1 Transcription Factors / metabolism
  • Signal Transduction
  • Skin Neoplasms / genetics
  • Skin Neoplasms / pathology
  • Transcription Factors / metabolism
  • Zinc Finger E-box-Binding Homeobox 1 / metabolism
  • src-Family Kinases / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Cadherins
  • Cd44 protein, mouse
  • FAT1 protein, human
  • Hyaluronan Receptors
  • Phosphoproteins
  • SOX2 protein, human
  • SOXB1 Transcription Factors
  • Transcription Factors
  • YAP1 protein, human
  • ZEB1 protein, mouse
  • Zinc Finger E-box-Binding Homeobox 1
  • fat1 protein, mouse
  • Enhancer of Zeste Homolog 2 Protein
  • Ezh2 protein, mouse
  • src-Family Kinases