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Open Access | 10.1172/jci.insight.170928
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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Pethő, Z.
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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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Najder, K.
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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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Fels, B.
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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
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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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Mitkovski, M.
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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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Published August 29, 2023 - More info
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.