A mechanically active heterotypic E-cadherin/N-cadherin adhesion enables fibroblasts to drive cancer cell invasion
journal contributionposted on 27.08.2020, 15:18 by Anna Labernadie, Takuya Kato, Agustí Brugués, Xavier Serra-Picamal, Stefanie Derzsi, Esther Arwert, Anne Weston, Victor González-Tarragó, Alberto Elosegui-Artola, Lorenzo Albertazzi, Jordi Alcaraz, Pere Roca-Cusachs, Erik Sahai, Xavier Trepat
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.
AdenocarcinomaAdenocarcinoma of LungBiomechanical PhenomenaCadherinsCancer-Associated FibroblastsCell AdhesionCell Adhesion MoleculesCell Line, TumorCell Migration AssaysCell MovementCell PolarityCoculture TechniquesFemaleHumansImaging, Three-DimensionalLung NeoplasmsMechanotransduction, CellularMicrofilament ProteinsNectinsNeoplasm InvasivenessNeoplasmsNeoplasms, Squamous CellOptical TweezersSpheroids, CellularVulvar NeoplasmsSahai FC001144EM06 Biological Sciences11 Medical and Health SciencesDevelopmental Biology