Caveolin-1 and mechanical stress control the release of a pro-metastatic subpopulation of small extracellular vesicles

Abstract

Mechanical forces within the tumor microenvironment critically influence cancer progression, in part by modulating extracellular vesicle (EV) dynamics. However, the molecular mechanisms by which EVs respond to mechanical cues remain poorly understood. Here, we identify caveolin-1 (Cav1), a core structural component of caveolae, specialized membrane invaginations that act as mechanosensors, as a key regulator of EV release and composition under mechanical stress. We demonstrate that both 2D osmotic shock and 3D mechanical compression significantly enhance EV secretion from cancer cells in a Cav1-dependent manner. These EVs exhibit a distinct lipid profile and are selectively enriched in proteins involved in cell adhesion, motility, wound healing and extracellular matrix remodeling, cargo that is lost upon Cav1 deletion. Functionally, EVs secreted from mechanically stressed cells preferentially accumulate in the liver in vivo and promote breast cancer cell migration and invasion in vitro, effects abolished in the absence of Cav1. Together, these findings reveal a previously unrecognized role for Cav1 in coupling mechanical stress to EV biogenesis and cargo loading, thereby promoting metastatic traits. This study underscores a novel mechanism by which mechanical cues within tumor environment regulate EV-mediated communication and suggests that Cav1-enriched EVs may contribute to pre-metastatic niche formation.