Fig. 3. ECM remodelling during tumour cell migration.

a In carcinoma in situ, tumour cells are restricted from migrating and invading into the surrounding tissue by the intact basement membrane. Tumour cells and stroma cells may be physically connected through the basement membrane using integrins. ECM in the interstitial matrix is curly. b Basement membrane breakage can be achieved through proteolytic ECM degradation by proteases secreted by tumour cells and activated stroma cells (top) and through non-proteolytic, force-mediated ECM remodelling (lower box). Integrins expressed on invadopodia, an invasive actin-rich cell structure on tumour and cancer-associated fibroblasts (CAFs), bind to ECM molecules and couple them intracellularly to contractile structures. This process pulls the ECM molecules apart and applies force to the basement membrane facilitating non-proteolytic basement membrane breaching. c In invasive tumours, the basement membrane is mostly degraded. CAFs and tumour cells secrete LOX to cross-link collagen fibres. Increased cross-linking and force-mediated ECM remodelling creates linearised ECM in the tumour-surrounding interstitial matrix. Tumour cells migrate along regions with dense, aligned collagen fibres forming migratory tracks for efficient cell migration. (lower box) Membrane-bound proteases expressed on tumour cells and CAFs, such as MT1-MMP localised on invadopodia, degrades the collagen migration barriers. Exosomes contain additional proteases to clear the ECM for tumour cell migration and are released into the interstitial matrix. Integrins on the surface of secreted exosomes bind to fibronectin, which functions as a bridging molecule connecting integrins expressed on tumour cells thereby promoting the formation of invadopodia and tumour cell migration. CAFs can function as leader cells for directed tumour cell migration and are connected to tumour cells through E-cadherin/N-cadherin adhesions.