Basement membrane turnover drives filopodial protease-independent invasion

The basement membrane is a specialised nanoporous extracellular matrix mainly composed of collagen IV fibres and laminins. As collagen IV fibres form covalent cross-links, cells cannot freely cross it. Basement membrane breaching marks the transition from in situ to invasive carcinoma, commonly attributed to protease activity. Yet, recent data show that tumour cells can cross basement membranes through protease-independent mechanisms. Experimental evidence suggests that filopodia can play an active role in pore enlargement in extracellular matrices by generating plastic mechanical deformation. Moreover, plasticity can be regulated by covalent cross-link concentration, which we hypothesise can be responsive to collagen IV turnover, thus generating transient weak spots. To test this, we developed a quantitative, biophysical mathematical model describing the interaction between a tumour-cell cluster and a basement membrane using relevant biological assumptions and parameters. The cluster is represented as an evolving, energetic surface and the basement membrane is described as a set of points representing active and inactive links. Simulations show that synchronisation of collagen IV turnover coupled with filopodium extension drives pore enlargement, providing a mechanistic basis for protease-independent invasion. Consistent with experiments, simulations identify two complementary filopodium groups: one driving global degradation and the other promoting local pore enlargement.