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

• Published in: Nature cell biology Vol. 19; no. 3; pp. 224 - 237
• Main Authors: Labernadie, Anna, Kato, Takuya, Brugués, Agustí, Serra-Picamal, Xavier, Derzsi, Stefanie, Arwert, Esther, Weston, Anne, González-Tarragó, Victor, Elosegui-Artola, Alberto, Albertazzi, Lorenzo, Alcaraz, Jordi, Roca-Cusachs, Pere, Sahai, Erik, Trepat, Xavier
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.03.2017
• Subjects: Adenocarcinoma - pathology; Adenocarcinoma of Lung; Biomechanical Phenomena; Cadherins; Cadherins - metabolism; Cancer; Cancer-Associated Fibroblasts - metabolism; Cancer-Associated Fibroblasts - pathology; Cancer-Associated Fibroblasts - ultrastructure; Carcinogenesis; Cell Adhesion; Cell Adhesion Molecules - metabolism; Cell Line, Tumor; Cell Migration Assays; Cell Movement; Cell Polarity; Cells; Cellular pathology; Coculture Techniques; Female; Fibroblasts; Genetic aspects; Health aspects; Humans; Imaging, Three-Dimensional; Lung Neoplasms - pathology; Mechanotransduction, Cellular; Microfilament Proteins; Nectins; Neoplasm Invasiveness; Neoplasms - metabolism; Neoplasms - pathology; Neoplasms, Squamous Cell - pathology; Optical Tweezers; Patologia cel·lular; Spheroids, Cellular - pathology; Tumors; Vulvar Neoplasms - pathology; Spain
• ISSN: 1465-7392; 1476-4679
• DOI: 10.1038/ncb3478

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.