The splanchnic mesenchyme is the tissue of origin for pancreatic fibroblasts during homeostasis and tumorigenesis
Open accessAbstract
Pancreatic cancer is characterized by abundant desmoplasia, a dense stroma composed of extra-cellular and cellular components, with cancer associated fibroblasts (CAFs) being the major cellular component. However, the tissue(s) of origin for CAFs remains controversial. Here we determine the tissue origin of pancreatic CAFs through comprehensive lineage tracing studies in mice. We find that the splanchnic mesenchyme, the fetal cell layer surrounding the endoderm from which the pancreatic epithelium originates, gives rise to the majority of resident fibroblasts in the normal pancreas. In a genetic mouse model of pancreatic cancer, resident fibroblasts expand and constitute the bulk of CAFs. Single cell RNA profiling identifies gene expression signatures that are shared among the fetal splanchnic mesenchyme, adult fibroblasts and CAFs, suggesting a persistent transcriptional program underlies splanchnic lineage differentiation. Together, this study defines the phylogeny of the mesenchymal component of the pancreas and provides insights into pancreatic morphogenesis and tumorigenesis.
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Wt1+ mesothelial cells contribute to a subpopulation of CAFs.
“mesothelial cells, expressing Wilms Tumor 1 (Wt1) also contribute to a sub-population of CAFs145”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [145]
apCAF transcriptional profiles overlap with mesothelial cells and are postulated to derive from a mesothelial origin.
“the transcriptional profiles of apCAFs overlap with mesothelial cells150, and based on lineage tracing studies in mice have been postulated to derive from a mesothelial origin145”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [145]
Combining several scRNA-seq datasets with lineage tracing showed that ap-CAFs may originate from mesothelium and drive regulatory T cell expansion and immune suppression.
“Integration of multiple scRNA-seq datasets combined with lineage tracing studies demonstrated that ap-CAFs can arise from a mesothelial origin and regulate the expansion of regulatory T cells and immune suppression145.”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [145]
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- [44]Han L The splanchnic mesenchyme is the tissue of origin for fibroblasts in the pancreas during homeostasis and tumorigenesis Zenodo 2022 10.5281/zenodo.7150239 PMC9810714 36596776 · DOI
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Pancreatic cancer: Advances and challenges
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- Authors
- Han, L., Wu, Y., Fang, K., Sweeney, S., Roesner, U. K., Parrish, M., Patel, K., Walter, T., Piermattei, J., Trimboli, A., Lefler, J., Timmers, C. D., Yu, X.-Z., Jin, V. X., Zimmermann, M. T., Mathison, A. J., Urrutia, R., Ostrowski, M. C., & Leone, G.
- Affiliations
- Medical University of South Carolina (US)
- Medical College of Wisconsin (US)
- Corresponding author
- Ostrowski, Michael C.
- Leone, Gustavo
- ORCID
- Venue
- Nature Communications
- Published
- 2023-01-03
- Volume
- 14
- Issue
- 1
- Pages
- 1-1
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC9810714
- OpenAlex
- W4313506857
- Cited by
- 369
- References
- 44
- Citations by year
- 2026: 77 · 2025: 169 · 2024: 92 · 2023: 22 · 2022: 6 · 2021: 3
- FWCI
- 43.65
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Dr. Glenn R. and Nancy A. Linnerson Endowed Fund
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Health Sciences › Medicine › Surgery › Pancreatitis Pathology and Treatment
- Keywords
- pancreatic fibroblasts, tissue of origin, lineage tracing, pancreatic stroma, desmoplasia, pancreatic morphogenesis, pancreatic carcinogenesis, single-cell RNA sequencing, transcriptional programs, mouse model
- MeSH terms
- Animals, Cell Transformation, Neoplastic, Fibroblasts, Homeostasis, Mesoderm, Pancreas, Pancreatic Neoplasms, Mice, Carcinogenesis
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