Journal
NATURE CELL BIOLOGY
Volume 19, Issue 3, Pages 224-237Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncb3478
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Funding
- Spanish Ministry of Economy and Competitiveness/FEDER [BFU2012-38146, BFU2014-52586-REDT, IJCI2014-19843, IJCI-2014-19156]
- Generalitat de Catalunya [2014-SGR-927]
- Generalitat de Catalunya (CERCA Programme)
- European Research Council [StG-CoG-616480]
- Obra Social 'La Caixa'
- Marie-Curie action [CAFFORCE 328664]
- EMBO Long-term fellowship [EMBO ALTF 1235-2012]
- Career Integration Grant within the seventh European Community Framework Programme [PCIG10-GA-2011-303848]
- Fundacio la Marato de TV3 [20133330]
- AXA research fund
- Francis Crick Institute
- Cancer Research UK [FC001144]
- UK Medical Research Council [FC001144]
- Wellcome Trust [FC001144]
- Marie-Curie action (HeteroCancerinvasion) [708651]
- Japanese Strategic Young Researcher Overseas Visits Program for Accelerating Brain Circulation
- The Francis Crick Institute [10482, C50839/A18100, 10004, 10146, 10144] Funding Source: researchfish
- Marie Curie Actions (MSCA) [708651] Funding Source: Marie Curie Actions (MSCA)
- ICREA Funding Source: Custom
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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 beta-catenin recruitment and adhesion reinforcement dependent on alpha-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.
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