Confinement Suppresses Mechanical Force‐Mediated Cancer Cell Apoptosis

Abstract During the invasion, cancer cells migrate through ‘3D channel‐like tracks’ present in the tissues' interstitial extracellular matrix (ECM). Cancer cell migration through these 3D confined channels leads to confinement‐induced cell deformation. Emerging reports show that cancer cells are susceptible to mechanical stretch/ultrasound (US)‐mediated mechanical forces and undergo calcium‐dependent apoptosis (mechanoptosis) under conditions that promote normal cell growth. Surprisingly, we find that confinement‐induced cell deformation suppresses mechanoptosis. Studies done using microchannel platforms and tumor spheroid models show that a low level of apoptosis is observed in confined cells. Further, apoptosis level is found to increase with a decrease in the degree of confinement. The absence of mature focal adhesions (FAs), low myosin IIA contractility, and diffuse mechanosensitive Piezo1 channels are responsible for a low level of apoptosis in confined cells. Thus, these findings suggest that confined cells, due to the absence of mature FAs, could not sense and transduce the mechanical forces and generate enough myosin IIA contractility required to initiate apoptosis. The combined action of US and activators of myosin contractility can be used to target invading cancer cells.