Polycystin-1 Orchestrates Tumor Context-Dependent Mechanotransduction Programs Driving Epithelial-to-Mesenchymal...

Mechanotransduction critically shapes tumor progression by regulating cytoskeletal remodeling, epithelial-to-mesenchymal transition (EMT), invasion, and immune evasion. Polycystin-1 (PC1) and polycystin-2 (PC2), established mechanosensitive proteins in epithelial systems, have recently been implicated in tumor biology; however, their roles across diverse solid malignancies remain insufficiently defined. We assessed PC1 and PC2 expression patterns and their associations with clinicopathological features in human lung, breast, prostate, and brain tumors. PC1 functional modulation was performed in xenograft models using an extracellular mechanosensitivity-blocking antibody, and in cancer cell lines via polycystic kidney disease 1 (PKD1) siRNA. We evaluated consequences on EMT, tumor growth, migration, and the mechanotransduction effector TAZ. PC1 and PC2 exhibited strong positive correlation across multiple tumor types, indicating coordinated mechanobiological regulation in cancer. Their expression associated with clinically aggressive features, including PD-L1 expression in lung cancer, adverse pathological characteristics in prostate cancer, and poorer survival in HER2⁺ breast cancer with elevated PC2 levels. In vivo, inhibition of PC1 mechanosensing consistently attenuated EMT programs across tumor types, accompanied by reductions in tumor growth. In vitro, PKD1 silencing reduced cell migration and induced context-dependent modulation of EMT markers. Notably, PC1 suppression induced TAZ activation in breast cancer and glioma cells, indicating a cell type-specific regulatory interaction between PC1 and Hippo-mechanotransduction signaling. Our data suggest that polycystins, PC1 in particular, exert conserved yet context-dependent mechanoregulatory functions in solid tumors. By influencing EMT, migration, tumor progression, and TAZ-mediated mechanotransduction, PC1 emerges as a potential biomarker and mechanotherapeutic target in mechanically responsive cancers.