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.

Examining Supramolecular Exchange: Microtubules are a natural example of a one-dimensional (1D) supramolecular structure. Synthetic examples of 1D fibrils often have monomers linked by weak noncovalent interactions that allow monomers to exchange in and out of the fibrils. Albertazzi et al. (p. 491 ) used a combination of super-resolution microscopy on individual fibrils and stochastic simulation to study monomer exchange in fibrils formed from stacked 1,3,5-benzenetricarboxamide motifs. Exchange did not require large-scale depolymerization and repolymerization, or reassembly of fragments, but proceeded through individual monomers exchanging homogeneously throughout the fibrils.