Cited by 239Pancreatic and Hepatic Oncology ResearchCancer Cells and MetastasisCellular Mechanics and Interactions

Mesenchymal lineage heterogeneity underlies nonredundant functions of pancreatic cancer-associated fibroblasts

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Helms, Erin J., Berry, Mark W., Chaw, R. Crystal, DuFort, Christopher C., Sun, Duanchen, Onate, M. Kathrina, Oon, Chet, Bhattacharyya, Sohinee +9 more·2022·Cancer Discovery

Published version of a preprint

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.
Venue
Cancer Discovery
Published
2021-09-21
Volume
12
Issue
2
Pages
484-501
ISSN
  • 2159-8274 (ISSN-L)
  • 2159-8290
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
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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