Shear stress increases acidic vesicles and proton pumps enhancing prostate cancer progression

Cells in the tumor microenvironment are subjected to increased interstitial fluid pressure due to the angiogenic growth of new leaky blood vessels which triggers lymphangiogenic growth for drainage. This subjects tumor cells to shear stresses of approximately 0.01-0.1 dynes/cm², two to three orders of magnitude smaller than wall shear stresses in blood vessels. While acidic membrane-bound vesicles, such as endosomes and lysosomes, and the V-ATPase proton pumps located on their membranes have been pursued as cancer markers, their role in cancer cell mechanotransduction and enhancing cancer aggressiveness is only recently emerging. We demonstrate that moderately metastatic prostate cancer cells respond to shear stress by increasing endosomes, lysosomes, and proton pumps, thereby activating both complexes of the mechanistic target of rapamycin pathway – mTORC1 and mTORC2 – controllers of autophagy, protein synthesis, glucose and lipid metabolism, and cell cytoskeletal changes. We will also report on shear stress-induced changes in migration and glucose metabolism, where increases accompany enhanced aggressiveness.