Recursive Feedback Between Matrix Dissipation and Chemo-mechanical Signaling Drives Oscillatory Growth of Cancer Cell Invadopodia

Most extracellular matrices (ECMs) are known to be dissipative, exhibiting viscoelastic and often plastic behaviors. However, the influence of dissipation on cell motility, in particular the plasticity in 3D environments that endows matrix with long-term mechanical memory, is not clear. Here, we develop a chemo-mechanical model to predict the impact of matrix plasticity on the dynamics of invadopodia, the protrusive structures that cancer cells use to facilitate invasion. We show that matrix dissipation facilitates invadopodia oscillations by softening the ECMs over repeated cycles, during which plastic deformation accumulates via cyclic ratcheting. Our model reveals that distinct patterns of protrusion behavior, oscillatory or monotonic, emerge from the interplay between extension-associated viscosity and signaling-associated myosin recruitment. We also predict and experimentally validate the influence of different drug treatments on invadopodia dynamics. More importantly, our model provides a quantitative framework to understand how ECMs can serve as a memory storage mechanism for protrusions that is “written on” or “read” by cells.