# Loss of TRPV4 reduces pancreatic cancer growth and metastasis

## TL;DR

Deleting TRPV4 in mice reduces pancreatic cancer growth and spread, suggesting TRPV4 blockers could be a new treatment.

## Contribution

The study shows that TRPV4 inhibition reduces tumor growth and metastasis in pancreatic cancer models.

## Key findings

- TRPV4-KO mice had smaller tumors and lower levels of inflammatory markers in PDAC models.
- TRPV4 deletion reduced liver microlesions and inflammatory cell clusters in mice.
- Blocking TRPV4 improved survival in multiple PDAC mouse models.

## Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a rapidly metastasizing cancer characterized by a dense desmoplastic stroma composed of extracellular matrix (ECM) proteins, which complicates treatment. Upon stimulation, pancreatic stellate cells (PSCs) differentiated 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 differentiated human PSCs into an inflammatory CAF phenotype that expresses chemoresistance and cancer stemness markers CD10 and GPR77. In an orthotopic PDAC model, TRPV4-KO mice exhibited a significant reduction in tumor size, circulating inflammatory cytokines, tissue inhibitor of metalloproteinases-1 (TIMP1), and premetastatic niche markers, serum amyloid A (SAA) proteins. A similar trend was observed in mice lacking functional PIEZO1 in PSCs. The livers of TRPV4-KO mice exhibited fewer cancer cell microlesions, lacked macrotumors, produced lower levels of inflammatory protein S100A8, and developed fewer inflammatory cell clusters. In orthotopic and genetically engineered models of PDAC, these mice also had improved survival, suggesting that blocking TRPV4 channels may be a promising therapeutic target for PDAC.

<span>TRPV4 deletion in mice significantly reduced PDAC growth, metastasis and improved survival, suggesting that a </span><span>TRPV4 blocker could be beneficial in treating PDAC patients.</span>