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ResearchIn-Press PreviewMetabolismOncology Open Access | 10.1172/jci.insight.170928

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

Zoltán Pethő,1 Karolina Najder,1 Stephanie Beel,2 Benedikt Fels,3 Ilka Neumann,1 Sandra Schimmelpfennig,1 Sarah Sargin,1 Maria Wolters,4 Klavs Grantins,4 Eva Wardelmann,4 Miso Mitkovski,5 Andrea Oeckinghaus,2 and Albrecht Schwab1

1Institute of Physiology II, University of Münster, Münster, Germany

2Institute of Molecular Tumor Biology, University of Münster, Münster, Germany

3Institute of Physiology, University of Lübeck, Lübeck, Germany

4Gerhard-Domagk-Institute of Pathology, University of Münster, Münster, Germany

5City Campus Light Microscopy Facility, Max Planck Institute for Multidisciplinary Sciences, Goettingen, Germany

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1Institute of Physiology II, University of Münster, Münster, Germany

2Institute of Molecular Tumor Biology, University of Münster, Münster, Germany

3Institute of Physiology, University of Lübeck, Lübeck, Germany

4Gerhard-Domagk-Institute of Pathology, University of Münster, Münster, Germany

5City Campus Light Microscopy Facility, Max Planck Institute for Multidisciplinary Sciences, Goettingen, Germany

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1Institute of Physiology II, University of Münster, Münster, Germany

2Institute of Molecular Tumor Biology, University of Münster, Münster, Germany

3Institute of Physiology, University of Lübeck, Lübeck, Germany

4Gerhard-Domagk-Institute of Pathology, University of Münster, Münster, Germany

5City Campus Light Microscopy Facility, Max Planck Institute for Multidisciplinary Sciences, Goettingen, Germany

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1Institute of Physiology II, University of Münster, Münster, Germany

2Institute of Molecular Tumor Biology, University of Münster, Münster, Germany

3Institute of Physiology, University of Lübeck, Lübeck, Germany

4Gerhard-Domagk-Institute of Pathology, University of Münster, Münster, Germany

5City Campus Light Microscopy Facility, Max Planck Institute for Multidisciplinary Sciences, Goettingen, Germany

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1Institute of Physiology II, University of Münster, Münster, Germany

2Institute of Molecular Tumor Biology, University of Münster, Münster, Germany

3Institute of Physiology, University of Lübeck, Lübeck, Germany

4Gerhard-Domagk-Institute of Pathology, University of Münster, Münster, Germany

5City Campus Light Microscopy Facility, Max Planck Institute for Multidisciplinary Sciences, Goettingen, Germany

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1Institute of Physiology II, University of Münster, Münster, Germany

2Institute of Molecular Tumor Biology, University of Münster, Münster, Germany

3Institute of Physiology, University of Lübeck, Lübeck, Germany

4Gerhard-Domagk-Institute of Pathology, University of Münster, Münster, Germany

5City Campus Light Microscopy Facility, Max Planck Institute for Multidisciplinary Sciences, Goettingen, Germany

Find articles by Schimmelpfennig, S. in: JCI | PubMed | Google Scholar

1Institute of Physiology II, University of Münster, Münster, Germany

2Institute of Molecular Tumor Biology, University of Münster, Münster, Germany

3Institute of Physiology, University of Lübeck, Lübeck, Germany

4Gerhard-Domagk-Institute of Pathology, University of Münster, Münster, Germany

5City Campus Light Microscopy Facility, Max Planck Institute for Multidisciplinary Sciences, Goettingen, Germany

Find articles by Sargin, S. in: JCI | PubMed | Google Scholar

1Institute of Physiology II, University of Münster, Münster, Germany

2Institute of Molecular Tumor Biology, University of Münster, Münster, Germany

3Institute of Physiology, University of Lübeck, Lübeck, Germany

4Gerhard-Domagk-Institute of Pathology, University of Münster, Münster, Germany

5City Campus Light Microscopy Facility, Max Planck Institute for Multidisciplinary Sciences, Goettingen, Germany

Find articles by Wolters, M. in: JCI | PubMed | Google Scholar

1Institute of Physiology II, University of Münster, Münster, Germany

2Institute of Molecular Tumor Biology, University of Münster, Münster, Germany

3Institute of Physiology, University of Lübeck, Lübeck, Germany

4Gerhard-Domagk-Institute of Pathology, University of Münster, Münster, Germany

5City Campus Light Microscopy Facility, Max Planck Institute for Multidisciplinary Sciences, Goettingen, Germany

Find articles by Grantins, K. in: JCI | PubMed | Google Scholar

1Institute of Physiology II, University of Münster, Münster, Germany

2Institute of Molecular Tumor Biology, University of Münster, Münster, Germany

3Institute of Physiology, University of Lübeck, Lübeck, Germany

4Gerhard-Domagk-Institute of Pathology, University of Münster, Münster, Germany

5City Campus Light Microscopy Facility, Max Planck Institute for Multidisciplinary Sciences, Goettingen, Germany

Find articles by Wardelmann, E. in: JCI | PubMed | Google Scholar

1Institute of Physiology II, University of Münster, Münster, Germany

2Institute of Molecular Tumor Biology, University of Münster, Münster, Germany

3Institute of Physiology, University of Lübeck, Lübeck, Germany

4Gerhard-Domagk-Institute of Pathology, University of Münster, Münster, Germany

5City Campus Light Microscopy Facility, Max Planck Institute for Multidisciplinary Sciences, Goettingen, Germany

Find articles by Mitkovski, M. in: JCI | PubMed | Google Scholar |

1Institute of Physiology II, University of Münster, Münster, Germany

2Institute of Molecular Tumor Biology, University of Münster, Münster, Germany

3Institute of Physiology, University of Lübeck, Lübeck, Germany

4Gerhard-Domagk-Institute of Pathology, University of Münster, Münster, Germany

5City Campus Light Microscopy Facility, Max Planck Institute for Multidisciplinary Sciences, Goettingen, Germany

Find articles by Oeckinghaus, A. in: JCI | PubMed | Google Scholar

1Institute of Physiology II, University of Münster, Münster, Germany

2Institute of Molecular Tumor Biology, University of Münster, Münster, Germany

3Institute of Physiology, University of Lübeck, Lübeck, Germany

4Gerhard-Domagk-Institute of Pathology, University of Münster, Münster, Germany

5City Campus Light Microscopy Facility, Max Planck Institute for Multidisciplinary Sciences, Goettingen, Germany

Find articles by Schwab, A. in: JCI | PubMed | Google Scholar

Published August 29, 2023 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.170928.
Copyright © 2023, Pethő et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published August 29, 2023 - Version history
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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 is 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 alters the myofibroblastic PSC phenotype. To show the relevance of this finding in vivo, we targeted NHE1 in murine PDAC (KPfC). Indeed, tumor fibrosis decreases when mice receive the NHE1-inhibitor cariporide in addition to gemcitabine treatment. Moreover, the tumor immune infiltrate shifts 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.

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  • Version 1 (August 29, 2023): In-Press Preview
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