Mechanosensing during Directed Cell Migration Requires Dynamic Actin Polymerization at Focal Adhesions

Abstract

The tumor microenvironment consists of a complex arrangement of both biochemical and mechanical components, which collectively regulate fundamental cellular processes including cell migration. The directional migration towards increasing matrix stiffness, durotaxis, has been implicated in processes ranging from development to cancer. Cells utilize specialized cell-matrix adhesions referred to as focal adhesions (FAs) to directly interact with extracellular matrix and dynamically sample its stiffness. Recent findings have proposed that the actomyosin cytoskeleton at FAs is central to an adhesion’s ability to sense mechanical stimuli (mechanosense). However, the mechanisms regulating actin dynamics at FAs are not fully understood. Here, we show that the Ena/VASP protein, EVL, polymerizes actin at FAs, which promotes cell-matrix adhesion and mechanosensing. Importantly, we show that EVL regulates the directional response to anisotropic mechanical stimulation, and that suppression of EVL expression impedes 3D durotactic invasion. Interestingly, we also show that while EVL promotes the response to mechanical stimuli, it impedes cellular response to biochemical stimulation. While future studies are needed to characterize the mechanisms of signal integration within a complex microenvironment, our work provides some of the first molecular characterization of durotaxis and provides evidence that chemically and mechanically directed migration are regulated by distinct and possibly antagonistic mechanisms.