A mechanically active heterotypic E-cadherin/N-cadherin adhesion enables fibroblasts to drive cancer cell invasion

Nat Cell Biol. 2017 Mar;19(3):224-237. doi: 10.1038/ncb3478. Epub 2017 Feb 20.


Cancer-associated fibroblasts (CAFs) promote tumour invasion and metastasis. We show that CAFs exert a physical force on cancer cells that enables their collective invasion. Force transmission is mediated by a heterophilic adhesion involving N-cadherin at the CAF membrane and E-cadherin at the cancer cell membrane. This adhesion is mechanically active; when subjected to force it triggers β-catenin recruitment and adhesion reinforcement dependent on α-catenin/vinculin interaction. Impairment of E-cadherin/N-cadherin adhesion abrogates the ability of CAFs to guide collective cell migration and blocks cancer cell invasion. N-cadherin also mediates repolarization of the CAFs away from the cancer cells. In parallel, nectins and afadin are recruited to the cancer cell/CAF interface and CAF repolarization is afadin dependent. Heterotypic junctions between CAFs and cancer cells are observed in patient-derived material. Together, our findings show that a mechanically active heterophilic adhesion between CAFs and cancer cells enables cooperative tumour invasion.

MeSH terms

  • Adenocarcinoma / pathology
  • Adenocarcinoma of Lung
  • Biomechanical Phenomena
  • Cadherins / metabolism*
  • Cancer-Associated Fibroblasts / metabolism*
  • Cancer-Associated Fibroblasts / pathology*
  • Cancer-Associated Fibroblasts / ultrastructure
  • Cell Adhesion
  • Cell Adhesion Molecules / metabolism
  • Cell Line, Tumor
  • Cell Migration Assays
  • Cell Movement
  • Cell Polarity
  • Coculture Techniques
  • Female
  • Humans
  • Imaging, Three-Dimensional
  • Lung Neoplasms / pathology
  • Mechanotransduction, Cellular
  • Microfilament Proteins
  • Nectins
  • Neoplasm Invasiveness
  • Neoplasms / metabolism
  • Neoplasms / pathology*
  • Neoplasms, Squamous Cell / pathology
  • Optical Tweezers
  • Spheroids, Cellular / pathology
  • Vulvar Neoplasms / pathology


  • Cadherins
  • Cell Adhesion Molecules
  • Microfilament Proteins
  • Nectins
  • afadin