The exocrine pancreas is comprised of enzyme-secreting acinar cells, fluid-secreting duct cells, and mesenchymal cells known as stellate cells. When the pancreas is injured, stellate cells become activated and produce collagen, fibronectin, and other proteins that comprise fibrosis. Pancreatic stellate cells (PSCs) are also a significant component of the pancreatic ductal adenocarcinoma (PDAC) tumor microenvironment. PSCs have the potential to differentiate into cancer-associated fibroblasts which secrete insoluble extracellular matrix (ECM) and other soluble proteins that stimulate cancer progression. Due to the stiffness of the ECM, mechanical forces are exerted within the tumor microenvironment as cells grow, producing both elevated tissue pressure and shear stress. We recently discovered that PSCs are exquisitely sensitive to pressure by virtue of their expression of the mechanically activated ion channel, Piezo1. Stimulation of Piezo1 by mechanical force or shear stress opens the channel and allows extracellular calcium to flow into the cell. In both mouse and human PSCs, we demonstrated that activation of Piezo1 converts cells to a cancer-associated fibroblast phenotype raising the possibility that blocking Piezo1 signaling would prevent conversion of PSCs to cancer-associated fibroblasts. The liver is the primary site for pancreatic cancer metastasis. Notably, the liver is primed to receive and harbor circulating tumor cells by soluble factors produced by the pancreatic cancer thus creating a liver ‘pro-metastatic niche’. Our preliminary data indicate that Piezo1 activation in PSCs due to elevated pressure/stiffness in fibrotic cancer tissue contributes to hepatic metastasis. We hypothesize that elevated intratumoral pressure stimulates Piezo1 in PSCs, converting them to a cancer- associated fibroblast phenotype. Activated PSCs produce soluble IL-6, IL-8, and other factors that induce a pro-metastatic niche within the liver, enhancing pancreatic cancer metastases. We will test this hypothesis in (i) PSCs in vitro, (ii) an orthotopic model of pancreatic cancer in vivo, and (iii) a genetically modified mouse model of PDAC using a combination of genetic and pharmacological tools to determine the role of mechanosensing and signaling within the pancreas and their contribution to pancreatic cancer metastasis. These studies will establish the mechanisms by which intrapancreatic mechanical forces that normally occur within PDAC generate a niche for liver metastases and may lead to novel therapies for pancreatic cancer which is a leading cause of cancer mortality in Veterans.