Recursive Feedback between Matrix Dissipation and Chemo-Mechanical Signaling Drives Oscillatory Growth of Cancer Cell Invadopodia

Abstract

As cells migrate through the extracellular matrix (ECM), they can sense the mechanical properties of their environment and remodel the matrix. Most 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 confining microenvironments that endows matrix with intrinsic long-term mechanical memory, is not clear. In this study, 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 and motility. By considering myosin dynamics, actin polymerization, adhesion formation, and biochemical signaling, we demonstrate that matrix dissipation facilitates invadopodia oscillations by softening the ECM over repeated cycles, during which plastic deformation gradually accumulates via cyclic ratcheting. Our model reveals that distinct patterns of protrusion behavior, oscillatory or monotonic, emerge from the interplay between timescales of extension-associated viscosity and signaling-associated myosin recruitment; oscillations are only observed when these timescales are comparable. Further, we predict and experimentally validate the influence of pharmacological treatments that target myosin activity, adhesions and Rho and Rho kinase (ROCK) pathways on invadopodia dynamics. More importantly, our model provides a quantitative framework to understand how the matrix can serve as a memory storage mechanism for protrusions that is “written on” or “read” by cells.