Loss of TRPV4 reduces pancreatic cancer growth and metastasis

Pancreatic ductal adenocarcinoma (PDAC) is a rapidly metastasizing cancer characterized by a dense desmoplastic stroma made up of extracellular matrix (ECM) proteins, which complicates treatment. Upon stimulation, pancreatic stellate cells (PSCs) differentiate into cancer-associated fibroblasts (CAFs) that are the source of ECM and cytokines in PDAC. We previously reported that mechanical stress activates PSCs and induces fibrosis through mechanical ion channel Piezo1-mediated TRPV4 channel activation, but its role in PDAC remains unclear. Here we report that pathological activation of Piezo1 differentiates human PSCs into an inflammatory CAF phenotype that expresses chemoresistance and cancer stemness markers CD10 and GPR77. In an orthotopic PDAC model, TRPV4 knockout mice exhibit a significant reduction in tumor size, circulating inflammatory cytokines, tissue inhibitor of metalloproteinases-1 (TIMP1), and pre-metastatic niche markers, serum amyloid A (SAA) proteins. A similar trend is observed in mice lacking functional Piezo1 in PSCs. The livers of TRPV4 knockout mice exhibit fewer cancer cell microlesions, lack macro tumors, produce lower levels of inflammatory protein S100A8, and develop fewer inflammatory cell clusters. In orthotopic and genetically engineered models of PDAC, these mice also have improved survival, suggesting that blocking TRPV4 channels may be a promising therapeutic target for PDAC. Overall design: RNA seq profiling of livers from WT and TRPV4 KO or WT treated with the GSK2193874 TRPV4 antogonist in a murine orthotopic model of PDAC. RNA seq profiling of mouse pancreatic stellate cells activatated by the PIEZO1 agonist Yoda1.