Tumor restriction by type I collagen opposes tumor-promoting effects of cancer-associated fibroblasts
Open accessAbstract
Cancer-associated fibroblasts (CAF) may exert tumor-promoting and tumor-suppressive functions, but the mechanisms underlying these opposing effects remain elusive. Here, we sought to understand these potentially opposing functions by interrogating functional relationships among CAF subtypes, their mediators, desmoplasia, and tumor growth in a wide range of tumor types metastasizing to the liver, the most common organ site for metastasis. Depletion of hepatic stellate cells (HSC), which represented the main source of CAF in mice and patients in our study, or depletion of all CAF decreased tumor growth and mortality in desmoplastic colorectal and pancreatic metastasis but not in nondesmoplastic metastatic tumors. Single-cell RNA-Seq in conjunction with CellPhoneDB ligand-receptor analysis, as well as studies in immune cell-depleted and HSC-selective knockout mice, uncovered direct CAF-tumor interactions as a tumor-promoting mechanism, mediated by myofibroblastic CAF-secreted (myCAF-secreted) hyaluronan and inflammatory CAF-secreted (iCAF-secreted) HGF. These effects were opposed by myCAF-expressed type I collagen, which suppressed tumor growth by mechanically restraining tumor spread, overriding its own stiffness-induced mechanosignals. In summary, mechanical restriction by type I collagen opposes the overall tumor-promoting effects of CAF, thus providing a mechanistic explanation for their dual functions in cancer. Therapeutic targeting of tumor-promoting CAF mediators while preserving type I collagen may convert CAF from tumor promoting to tumor restricting.
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HSCs also promote the growth of cholangiocarcinoma and desmoplastic liver metastases.
“In addition to promoting HCC, HSCs also promote the growth of cholangiocarcinoma and desmoplastic liver metastases [279, 280].”
From Inflammation and immunity in liver homeostasis and disease: a nexus of hepatocytes, nonparenchymal cells and immune cells (2025) · cites this paper as [280]
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- Authors
- Bhattacharjee, S., Hamberger, F., Ravichandra, A., Miller, M., Nair, A., Affo, S., Filliol, A., Chin, L., Savage, T. M., Yin, D., Wirsik, N. M., Mehal, A., Arpaia, N., Seki, E., Mack, M., Zhu, D., Sims, P. A., Kalluri, R., Stanger, B. Z., Olive, K. P., Schmidt, T., Wells, R. G., Mederacke, I., & Schwabe, R. F.
- Affiliations
- Columbia University (US)
- Medizinische Hochschule Hannover (DE)
- Rutgers, The State University of New Jersey (US)
- University of Pennsylvania (US)
- Heidelberg University (DE)
- Herbert Irving Comprehensive Cancer Center (US)
- Cedars-Sinai Medical Center (US)
- University Hospital Regensburg (DE)
- Fudan University (CN)
- The University of Texas MD Anderson Cancer Center (US)
- ORCID
- Bhattacharjee, Sonakshi
- Ravichandra, Aashreya
- Miller, Maximilian
- Nair, Ajay
- Affo, Silvia
- Filliol, Aveline
- Chin, LiKang
- Savage, Thomas M.
- Yin, Deqi
- Arpaia, Nicholas
- Seki, Ekihiro
- Mack, Matthias
- Zhu, Di
- Sims, Peter A.
- Kalluri, Raghu
- Stanger, Ben Z.
- Olive, Kenneth P.
- Schmidt, Thomas
- Wells, Rebecca G.
- Mederacke, Ingmar
- Schwabe, Robert F.
- Venue
- Journal of Clinical Investigation
- Published
- 2021-06-01
- Volume
- 131
- Issue
- 11
- ISSN
- 0021-9738 (ISSN-L)
- 1558-8238
- PMC
- PMC8159701
- OpenAlex
- W3157116981
- Cited by
- 367
- References
- 51
- Citations by year
- 2026: 56 · 2025: 86 · 2024: 93 · 2023: 58 · 2022: 56 · 2021: 18
- FWCI
- 20.76
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- University of Regensburg Publication Server (University of Regensburg) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- American Liver Foundation (ME 3723/1-1)
- American Gastroenterological Association (R01DK085252)
- Cholangiocarcinoma Foundation
- Deutsche Forschungsgemeinschaft (P30CA013696, ME 3723/1-1, ME 3723/2‐1)
- National Institutes of Health
- National Cancer Institute (U54CA193417, P01CA233452, R01CA190844, R01CA228483, P01CA117969, P30CA013696)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK085252)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Keywords
- cancer-associated fibroblasts, type I collagen, tumor microenvironment, desmoplasia, hepatic stellate cells, liver metastasis, colorectal cancer, pancreatic cancer, hyaluronic acid, hepatocyte growth factor, mechanotransduction, tumor stiffness
- MeSH terms
- Cancer-Associated Fibroblasts, Animals, Humans, Liver Neoplasms, Experimental, Neoplasm Metastasis, Mice, Knockout, Collagen Type I, Mechanotransduction, Cellular, Cell Line, Tumor, Mice, Hepatic Stellate Cells
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