Fluid shear stress facilitates prostate cancer metastasis through Piezo1-Src-YAP axis

Abstract Background Mechanical forces surrounding solid tumors are pervasive in the tumor microenvironment (TME) and abnormally altered as solid tumors progress. Although it has been reported that biomechanical forces, including wall shear stress (WSS), enhance the metastatic features of cancer cells, the mechanism by which cancer cells sense mechanical stress and propagate signals in the TME remains unknown. Methods Using a microfluidic device, interstitial fluid-mimicking flow (0.05 dyne cm− 2) was applied to the human prostate cancer cell line PC3. Piezo1 expression was detected using immunofluorescence and qRT-PCR. Piezo1 siRNA and shRNA lentivirus were applied to PC3 cells to ablate Piezo1 expression. PC3-Luc2 cells expressing control shRNA or shPiezo1 lentivirus were administered into the prostate of BALB/c mice for orthotopic injection, and metastatic prostate cancer cells were tracked by in vivo imaging for 6 weeks. Results Here, we show that Piezo1, a mechanosensitive ion channel, is activated by WSS in microfluidic channels. Moreover, Yoda1, a Piezo1 agonist, synergistically potentiates cancer cell motility via WSS. Yoda1 further increased WSS-mediated translocation of YAP/TAZ from the cytosol to the nucleus compared to WSS alone. Conversely, depleting Piezo1 with siRNA significantly reduced cell motility induced by WSS and inhibited nuclear retention of YAP/TAZ. Moreover, activation of Piezo1 increased phosphorylation of Src on Y416, which regulates phosphorylation of YAP on Y357, whereas ablation of Piezo1 with siRNA failed to induce Src phosphorylation and YAP activation. Furthermore, mice bearing control PC3-Luc2 showed rapid tumor growth and metastasis throughout the body, while this gradually decreased with the injection of shPiezo1 lentivirus into control PC3-Luc2-bearing BALB/c mice. Conclusions Taken together, these results demonstrate that Piezo1 allows cancer cells to sense mechanical stimuli by altering the microenvironment during tumor progression and is a critical player in modulating cancer metastasis through the Piezo1-Src-YAP axis.