LAUSR

Tumor cells metastasizing through the bloodstream or lymphatic systems must withstand acute shear stress (ASS). Autophagy is a cell survival mechanism that functions in response to stressful conditions, but also contributes to cell death or apoptosis. We predicted that a compensation pathway to autophagy exists in tumor cells subjected to mechanical stress. We found that ASS promoted autophagosome (AP) accumulation and induced release of extracellular nanovesicles (EVs) containing autophagy components. Furthermore, we found that ASS promoted autophagic vesicles fused with multivesicular body (MVB) to form an AP-MVB compartment and then induced autophagy component release into the extracellular space via EVs through the autophagy-MVB-exosome pathway. More importantly, either increasing intracellular autophagosome accumulation or inhibiting autophagic degradation promoted AP-MVB accumulation but did not induce autophagy-associated protein release via EVs except under ASS, demonstrating the existence of a mechanical stress-dependent compensation pathway. Together, these findings revealed that EVs provide an additional protection mechanism for tumor cells and counteract autophagy to maintain cellular homeostasis under acute shear stress.