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| Status |
Public on Sep 18, 2023 |
| Title |
Acid-base homeostasis orchestrated by NHE1 defines the pancreatic stellate cell phenotype in pancreatic cancer |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
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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| Overall design |
Comparative gene expression profiling analysis of RNA-seq data for C57BL6/J mouse-derived pancreatic stellate cells (PSCs), cultured for 120h at pH6.6 or at pH7.4. 3 biological replicates are included for each group.
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| Web link |
https://insight.jci.org/articles/view/170928
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| Contributor(s) |
Pethö Z, Schwab A |
| Citation(s) |
37643024 |
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| Submission date |
Jan 18, 2023 |
| Last update date |
Sep 18, 2023 |
| Contact name |
Zoltan Pethö |
| E-mail(s) |
pethoe@uni-muenster.de
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| Organization name |
University of Münster
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| Department |
Physiology II
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| Lab |
Cell Migration Lab
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| Street address |
Robert-Koch Str. 27B
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| City |
Münster |
| State/province |
NRW |
| ZIP/Postal code |
48149 |
| Country |
Germany |
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| Platforms (1) |
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| Samples (6)
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| GSM6943365 |
Pancreatic stellate cells, pH6.6, 120h, biol. replicate A |
| GSM6943366 |
Pancreatic stellate cells, pH6.6, 120h, biol. replicate B |
| GSM6943367 |
Pancreatic stellate cells, pH6.6, 120h, biol. replicate C |
| GSM6943368 |
Pancreatic stellate cells, pH7.4, 120h, biol. replicate A |
| GSM6943369 |
Pancreatic stellate cells, pH7.4, 120h, biol. replicate B |
| GSM6943370 |
Pancreatic stellate cells, pH7.4, 120h, biol. replicate C |
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| Relations |
| BioProject |
PRJNA925210 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE223205_PSC_pH_RNAseq_counts.xlsx |
1.8 Mb |
(ftp)(http) |
XLSX |
| GSE223205_PSC_pH_RNAseq_processed.xlsx |
1.6 Mb |
(ftp)(http) |
XLSX |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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