Mesenchymal lineage heterogeneity underlies nonredundant functions of pancreatic cancer-associated fibroblasts
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Abstract
Cancer-associated fibroblast (CAF) heterogeneity is increasingly appreciated, but the origins and functions of distinct CAF subtypes remain poorly understood. The abundant and transcriptionally diverse CAF population in pancreatic ductal adenocarcinoma (PDAC) is thought to arise from a common cell of origin, pancreatic stellate cells (PSC), with diversification resulting from cytokine and growth factor gradients within the tumor microenvironment. Here we analyzed the differentiation and function of PSCs during tumor progression in vivo. Contrary to expectations, we found that PSCs give rise to a numerically minor subset of PDAC CAFs. Targeted ablation of PSC-derived CAFs within their host tissue revealed nonredundant functions for this defined CAF population in shaping the PDAC microenvironment, including production of specific extracellular matrix components and tissue stiffness regulation. Together, these findings link stromal evolution from distinct cells of origin to transcriptional heterogeneity among PDAC CAFs and demonstrate unique functions for CAFs of a defined cellular origin. Significance: By tracking and ablating a specific CAF population, we find that a numerically minor CAF subtype from a defined cell of origin plays unique roles in establishing the pancreatic tumor microenvironment. Together with prior studies, this work suggests that mesenchymal lineage heterogeneity and signaling gradients diversify PDAC CAFs. See related commentary by Cukierman, p. 296. This article is highlighted in the In This Issue feature, p. 275
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Fabp4+ stellate cells give rise to a minority of CAFs.
“recent lineage tracing studies targeting Fabp4+ stellate cells revealed that they give rise to a minority of CAFs142,143”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [142]
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- Authors
- Helms, E. J., Berry, M. W., Chaw, R. C., DuFort, C. C., Sun, D., Onate, M. K., Oon, C., Bhattacharyya, S., Sanford-Crane, H., Horton, W., Finan, J. M., Sattler, A., Makar, R., Dawson, D. W., Xia, Z., Hingorani, S. R., & Sherman, M. H.
- Affiliations
- Oregon Health & Science University (US)
- Fred Hutch Cancer Center (US)
- 1Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, Oregon.
- University of California, Los Angeles (US)
- University of Washington (US)
- Corresponding author
- Sherman, Mara H.
- ORCID
- Venue
- Cancer Discovery
- Published
- 2021-09-21
- Volume
- 12
- Issue
- 2
- Pages
- 484-501
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC8831457
- OpenAlex
- W3199988150
- Cited by
- 238
- References
- 59
- Citations by year
- 2026: 41 · 2025: 49 · 2024: 52 · 2023: 54 · 2022: 34 · 2021: 8
- FWCI
- 13.57
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cancer Discovery (publishedVersion, cc-by-nc-nd)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- National Institute of General Medical Sciences (T32 GM071338)
- National Cancer Institute (R01 CA161112, U01 CA224193, R01 CA250917)
- U.S. Department of Defense (W81XWH-18-1-0437)
- Pew Charitable Trusts
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
- Keywords
- cancer-associated fibroblasts, pancreatic ductal adenocarcinoma, pancreatic stellate cells, CAF heterogeneity, mesenchymal lineage, tumor microenvironment, extracellular matrix, tissue stiffness, cell of origin
- MeSH terms
- Cancer-Associated Fibroblasts, Animals, Female, Humans, Male, Pancreatic Neoplasms, Gene Expression Regulation, Neoplastic, Mice, Mesenchymal Stem Cells
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