Loss of TRPV4 reduces pancreatic cancer growth and metastasis
Joelle M.-J. Romac, Sandip M. Swain, Nidula Mullappilly, Bandana Bindhani, Rodger A. Liddle
Joelle M.-J. Romac, Sandip M. Swain, Nidula Mullappilly, Bandana Bindhani, Rodger A. Liddle
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Research Article Gastroenterology Oncology

Loss of TRPV4 reduces pancreatic cancer growth and metastasis

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.

Authors

Joelle M.-J. Romac, Sandip M. Swain, Nidula Mullappilly, Bandana Bindhani, Rodger A. Liddle

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Figure 8

Effects of TRPV4 on pancreatic cancer survival.

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Effects of TRPV4 on pancreatic cancer survival. (A) Survival curve of WT...
(A) Survival curve of WT and TRPV4-KO mice following orthotopic injection of KPCY cells (10,000 cells) into the pancreas. Mice were monitored 3 times per week for signs of distress. (B) Pie charts of survivors versus nonsurvivors at the end of the experiment (120 days) for WT (red) and TRPV4 KO (blue) mice. (C) Nonsurvivor mice pancreas tumor weight WT and TRPV4 KO at the time of their death. (D) Representative images of livers from WT mice with metastatic tumor (upper panels) and TRPV4-KO mice (lower panels). Scale bars: 1 mm. Serial sections were stained with H&E or Masson’s trichrome dye (left panels) and immunostained with GFP (marking KCPY cells) and MPO antibodies (right panels). (E) Computation of macroscopic tumor, small tumors, and tumor cell clusters from liver tissues of nonsurviving animals: n = 13 for WT and n = 5 for TRPV4 KO. (F) Quantitative analysis of MPO+ cell clusters (≥10 cells) from images of liver sections. MOP+ cells present in the tumors were excluded from the cell count. Comparison of survival curves was performed using the Log-Rank (Mantel-Cox) test. Statistical analysis was performed using Student’s t test. Results were expressed as mean ± SEM. *P ≤ 0.05.