Acid-base homeostasis orchestrated by NHE1 defines the pancreatic stellate cell phenotype in pancreatic cancer
Zoltán Pethő, … , Andrea Oeckinghaus, Albrecht Schwab
Zoltán Pethő, … , Andrea Oeckinghaus, Albrecht Schwab
Published August 29, 2023
Citation Information: JCI Insight. 2023;8(19):e170928. https://doi.org/10.1172/jci.insight.170928.
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Research Article Metabolism Oncology

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

Abstract

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

Authors

Zoltán Pethő, Karolina Najder, Stephanie Beel, Benedikt Fels, Ilka Neumann, Sandra Schimmelpfennig, Sarah Sargin, Maria Wolters, Klavs Grantins, Eva Wardelmann, Miso Mitkovski, Andrea Oeckinghaus, Albrecht Schwab

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Figure 5

NHE1 inhibitor treatment leads to reduced desmoplastic reaction in murine PDAC.

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NHE1 inhibitor treatment leads to reduced desmoplastic reaction in murin...
(A) Schematic representation of the 4-week–long treatment protocol of KPfC mice. Treatment started at the age of week 20. Cariporide was applied daily (1/D), and gemcitabine (100 mg/kg i.p.) was coinjected with cariporide (3 mg/kg i.p.) on the days indicated by the arrows. (B) Total pancreas volume of KPfC mice after gemcitabine (GEM) or cariporide (CARI) monotherapy or gemcitabine + cariporide (GEM+CARI) combined chemotherapy. Inlet demonstrates that pancreas volume was measured via volume displacement. Data points depict individual pancreata; NVehicle = 11, NGEM = 9, NCARI = 11, NGEM+CARI = 11. (C) Relative tumor area in histological KPfC tissue sections was obtained by dividing total tumor area by total tissue area after H&E staining. Data points depict individual pancreata; NVehicle = 11, NGEM = 9, NCARI = 11, NGEM+CARI = 11. (D) Representative images of PDAC nodes (marked with *) after H&E and Sirius red stainings. The degree of fibrosis correlates with the area of Sirius red+ (marked in red, #) tissue neighboring the cancerous tissue. Scale bar: 100 μm. (E) Relative tumor fibrosis of each Sirius red–stained KPfC tissue section was determined by dividing the summed area of fibrosis within every tumor node (sum of thresholded black areas in every node in the inlet) by the summed area of the tumor nodes. Data points depict individual pancreata; NVehicle = 11, NGEM = 9, NCARI = 11, NGEM+CARI = 12. (F) To obtain the fibrosis per tumor node, the area of Sirius red+ fibrosis (black thresholded area in the inlet) was divided by the total area of the respective tumor node. Data points depict individual tumor nodes; nVehicle = 400, nGEM = 239, nCARI = 279, nGEM+CARI = 476. Data and statistical comparison in B, C, and F are shown as median ± 95% CI with Kruskal-Wallis statistical test with Dunn’s post hoc test, and in E as mean ± SEM with 1-way ANOVA with Tukey’s post hoc test. Inlets for A and B were created with BioRender.com.