Abstract
Cancer metastasis remains a leading cause of mortality, driven by mechanical cues from the tumor microenvironment. The mechanosensitive ion channel Piezo1 and focal adhesion kinase (FAK) are key transducers of mechanical signals, yet their functional interplay in metastasis is poorly understood. This study investigates the role of Piezo1 in regulating FAK signaling during cancer cell migration and invasion. Using in vitro models of breast and prostate cancer, we demonstrate that Piezo1 activation by substrate stiffness or the agonist Yoda1 enhances FAK phosphorylation at Tyr397 and downstream activation of ERK1/2 and AKT. Pharmacological inhibition of Piezo1 with GsMTx4 or siRNA-mediated knockdown reduces FAK activation and suppresses cell migration and invasion. Co-immunoprecipitation reveals a physical association between Piezo1 and FAK, which is potentiated under mechanical stimulation. Furthermore, Piezo1-mediated calcium influx is required for FAK activation, as chelating intracellular calcium or blocking calcium channels abrogates the effect. In 3D invasion assays, Piezo1 knockdown decreases metastatic potential, while FAK overexpression partially rescues the phenotype. Our findings identify a novel mechanotransduction pathway wherein Piezo1 activates FAK signaling to promote metastasis, suggesting that targeting Piezo1 may offer therapeutic strategies for metastatic cancer.