Acid-base homeostasis orchestrated by NHE1 defines the pancreatic stellate cell phenotype in pancreatic cancer

• DOI: 10.1172/jci.insight.170928
• Publication Date: 2023-08-29T16:02:05Z
• Authors: Zoltán Pethő; Karolina Najder; Stephanie Beel; Benedikt Fels; Ilka Neumann; Sandra Schimmelpf...; Sarah Sargin; Maria Wolters; Klavs Grantins; Eva Wardelmann; Miso Mitkovski; Andrea Oeckinghaus; Albrecht Schwab
• Keywords: Homeostasis; Hepatic stellate cell

Pancreatic ductal adenocarcinoma (PDAC) progresses in an organ with a unique pH landscape, where the stroma acidifies after each meal. We hypothesized that disrupting this landscape during PDAC progression triggers pancreatic stellate cells (PSCs) and cancer-associated fibroblasts (CAFs) to induce fibrosis. revealed alkaline environmental was sufficient PSC differentiation myofibroblastic phenotype. then mechanistically dissected finding, focusing on involvement of Na+/H+ exchanger NHE1. Perturbing cellular homeostasis by inhibiting NHE1 cariporide partially altered To show relevance finding vivo, we targeted murine (KPfC). Indeed, tumor fibrosis decreased when mice received NHE1-inhibitor addition gemcitabine treatment. Moreover, immune infiltrate shifted from granulocyte rich more lymphocytic. Taken together, our study provides mechanistic evidence how shapes cancer through tuning differentiation.