Matrix mechanical plasticity regulates cancer cell migration through confining microenvironments

TLDR

Cancer cell migration occurs via protease‑independent squeezing through micron‑sized pores or protease‑dependent degradation of nanoporous matrices, but many extracellular matrices are viscoelastic and plastically deform, making pore size variable. This study investigates how matrix plasticity influences cancer cell migration. The authors created interpenetrating network hydrogels with tunable plasticity but constant stiffness, and observed that cells in highly plastic IPNs extend invadopodia to mechanically open micron‑sized channels for migration. High plasticity IPNs enable a novel protease‑independent migration mode, where cells can traverse confining matrices by plastically creating channels.

Abstract

Abstract Studies of cancer cell migration have found two modes: one that is protease-independent, requiring micron-sized pores or channels for cells to squeeze through, and one that is protease-dependent, relevant for confining nanoporous matrices such as basement membranes (BMs). However, many extracellular matrices exhibit viscoelasticity and mechanical plasticity, irreversibly deforming in response to force, so that pore size may be malleable. Here we report the impact of matrix plasticity on migration. We develop nanoporous and BM ligand-presenting interpenetrating network (IPN) hydrogels in which plasticity could be modulated independent of stiffness. Strikingly, cells in high plasticity IPNs carry out protease-independent migration through the IPNs. Mechanistically, cells in high plasticity IPNs extend invadopodia protrusions to mechanically and plastically open up micron-sized channels and then migrate through them. These findings uncover a new mode of protease-independent migration, in which cells can migrate through confining matrix if it exhibits sufficient mechanical plasticity.