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

Abstract

Extracellular vesicles are lipid-enclosed vesicles released by most cells and are present in all human bodily fluids. EVs carry genetic material and proteins, which can be transferred to other cells, generating various biological effects. Caveolin-1 (Cav1) is a key structural protein of the small invaginations of the plasma membrane known as caveolae, which function as mechano-sensors and membrane tension buffering devices. Elevated levels of Cav1 have been detected in EVs from patients with advanced cancer. Given the importance of mechanical forces within the tumor microenvironment, we investigated the potential role of caveolae and/or Cav1 in regulating EV dynamics and cancer progression under mechanical stress. Our study revealed that different types of mechanical stress induced significantly increased the release of EVs from several cancer cell lines. These EVs were characterized as exosomes enriched with Cav1. Notably, we found that functional Cav1 was essential for the stress-induced increase in EV production. Lipidomic and proteomic analyses showed differences in the composition of EVs between WT and Cav1-deficient cells and between resting cells and cells subjected to mechanical stress. Additionally, EVs isolated from mechanically stressed cells were shown to promote enhanced migration and invasion of cancer cells in a Cav1-dependent manner. Altogether, our data uncover a new role for Cav1 in mediating cell-to-cell communication and promoting the acquisition of metastatic traits through the mechanical regulation of EV production and dynamics.