title: A mechanically active heterotypic E-cadherin/N-cadherin adhesion enables fibroblasts to drive cancer cell invasion.
abstract: 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.
authors.affiliation: Institute for Bioengineering of Catalonia, Barcelona 08028, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Labernadie
authors.affiliation: The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
authors.forename: Takuya
authors.initials: T
authors.lastname: Kato
authors.affiliation: Institute for Bioengineering of Catalonia, Barcelona 08028, Spain.
authors.forename: Agustí
authors.initials: A
authors.lastname: Brugués
authors.affiliation: Institute for Bioengineering of Catalonia, Barcelona 08028, Spain.|Unitat de Biofísica i Bioenginyeria, Facultat de Medicina, Universitat de Barcelona, Barcelona 08036, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Serra-Picamal
authors.affiliation: The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Derzsi
authors.affiliation: The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
authors.forename: Esther
authors.initials: E
authors.lastname: Arwert
authors.affiliation: The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
authors.forename: Anne
authors.initials: A
authors.lastname: Weston
authors.affiliation: Institute for Bioengineering of Catalonia, Barcelona 08028, Spain.
authors.forename: Victor
authors.initials: V
authors.lastname: González-Tarragó
authors.affiliation: Institute for Bioengineering of Catalonia, Barcelona 08028, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Elosegui-Artola
authors.affiliation: Institute for Bioengineering of Catalonia, Barcelona 08028, Spain.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Albertazzi
authors.affiliation: Unitat de Biofísica i Bioenginyeria, Facultat de Medicina, Universitat de Barcelona, Barcelona 08036, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Alcaraz
authors.affiliation: Institute for Bioengineering of Catalonia, Barcelona 08028, Spain.|Unitat de Biofísica i Bioenginyeria, Facultat de Medicina, Universitat de Barcelona, Barcelona 08036, Spain.
authors.forename: Pere
authors.identifier: 0000-0001-6947-961X
authors.initials: P
authors.lastname: Roca-Cusachs
authors.affiliation: The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
authors.forename: Erik
authors.initials: E
authors.lastname: Sahai
authors.affiliation: Institute for Bioengineering of Catalonia, Barcelona 08028, Spain.|Unitat de Biofísica i Bioenginyeria, Facultat de Medicina, Universitat de Barcelona, Barcelona 08036, Spain.|Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona 08010, Spain.|Centro de Investigación Biomédica en Red en Bioingeniería, Biomateriales y Nanomedicina, Barcelona 08028, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Trepat
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D001696:Biomechanical Phenomena; D015820:Cadherins / Q000378:metabolism*; D000072645:Cancer-Associated Fibroblasts / Q000378:metabolism* / Q000473:pathology* / Q000648:ultrastructure; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000378:metabolism; D045744:Cell Line, Tumor; D054443:Cell Migration Assays; D002465:Cell Movement; D016764:Cell Polarity; D018920:Coculture Techniques; D005260:Female; D006801:Humans; D021621:Imaging, Three-Dimensional; D008175:Lung Neoplasms / Q000473:pathology; D040542:Mechanotransduction, Cellular; D008840:Microfilament Proteins; D000075983:Nectins; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology*; D018307:Neoplasms, Squamous Cell / Q000473:pathology; D052898:Optical Tweezers; D018874:Spheroids, Cellular / Q000473:pathology; D014846:Vulvar Neoplasms / Q000473:pathology
chemical_list: D015820:Cadherins; D015815:Cell Adhesion Molecules; D008840:Microfilament Proteins; D000075983:Nectins; C108835:afadin