Promotion of cholangiocarcinoma growth by diverse cancer-associated fibroblast subpopulations
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Cancer-associated fibroblasts (CAF) are a poorly characterized cell population in the context of liver cancer. Our study investigates CAF functions in intrahepatic cholangiocarcinoma (ICC), a highly desmoplastic liver tumor. Genetic tracing, single-cell RNA sequencing, and ligand-receptor analyses uncovered hepatic stellate cells (HSC) as the main source of CAF and HSC-derived CAF as the dominant population interacting with tumor cells. In mice, CAF promotes ICC progression, as revealed by HSC-selective CAF depletion. In patients, a high panCAF signature is associated with decreased survival and increased recurrence. Single-cell RNA sequencing segregates CAF into inflammatory and growth factor-enriched (iCAF) and myofibroblastic (myCAF) subpopulations, displaying distinct ligand-receptor interactions. myCAF-expressed hyaluronan synthase 2, but not type I collagen, promotes ICC. iCAF-expressed hepatocyte growth factor enhances ICC growth via tumor-expressed MET, thus directly linking CAF to tumor cells. In summary, our data demonstrate promotion of desmoplastic ICC growth by therapeutically targetable CAF subtype-specific mediators, but not by type I collagen.
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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 [279]
In damaged and inflammatory liver, quiescent HSCs activate into proliferative, contractile, ECM-remodeling myofibroblasts that also secrete cytokines and chemokines.
“In the presence of signals from the damaged and inflammatory liver, quiescent HSCs “activate” into proliferative, contractile, ECM-remodeling myofibroblasts that also harbor inflammatory features through the secretion of cytokines and chemokines (96) (97, 98).”
From Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH) (2023) · cites this paper as [98]
In liver cancer models, different subsets of HSC-derived cancer-associated fibroblasts have divergent functions that can either promote or attenuate cancer.
“In models of liver cancer (both cholangiocarcinoma and hepatocellular carcinoma) different subsets of HSC-derived cancer-associated fibroblasts (CAFs) have divergent functions that can either promote or attenuate cancer (97, 98).”
From Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH) (2023) · cites this paper as [98]
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Sugimoto, A., Saito, Y., Wang, G., Sun, Q., Yin, C., Lee, K. H., Geng, Y., Rajbhandari, P., Hernandez, C., Steffani, M., et al. (2025) · Nature · doi:10.1038/s41586-025-08677-w · Cited by 110 · see citing works
Self-citationFibroblasts in liver cancer: functions and therapeutic translation
Affo, S., Filliol, A., Gores, G. J., & Schwabe, R. F. (2023) · The Lancet Gastroenterology & Hepatology · doi:10.1016/s2468-1253(23)00111-5 · Cited by 49 · see citing works
Self-citationTrinh, V. Q.-H., Lee, T.-F., Lemoinne, S., Ray, K. C., Ybanez, M. D., Tsuchida, T., Carter, J. K., Agudo, J., Brown, B. D., Akat, K. M., et al. (2023) · Science Signaling · doi:10.1126/scisignal.adf6696 · Cited by 45 · see citing works
St. Rose, K., Yan, J., Xu, F., Williams, J., Dweck, V., Saxena, D., Schwabe, R. F., & Caviglia, J. M. (2022) · Hepatology Communications · doi:10.1002/hep4.2035 · Cited by 14 · see citing works
Self-citationLi, Z., Ma, L., Chen, M., Chen, X., Sha, M., & Hang, H. (2025) · JHEP Reports · doi:10.1016/j.jhepr.2024.101275 · Cited by 11 · see citing works
Self-citation
- Authors
- Affo, S., Nair, A., Brundu, F., Ravichandra, A., Bhattacharjee, S., Matsuda, M., Chin, L., Filliol, A., Wen, W., Song, X., Decker, A., Worley, J., Caviglia, J. M., Yu, L., Yin, D., Saito, Y., Savage, T., Wells, R. G., Mack, M., Zender, L., Arpaia, N., Remotti, H. E., Rabadan, R., Sims, P., Leblond, A.-L., Weber, A., Riener, M.-O., Stockwell, B. R., Gaublomme, J., Llovet, J. M., Kalluri, R., Michalopoulos, G. K., Seki, E., Sia, D., Chen, X., Califano, A., & Schwabe, R. F.
- Affiliations
- Columbia University Irving Medical Center (US)
- Columbia University (US)
- Cedars-Sinai Medical Center (US)
- University of Pennsylvania (US)
- University of California, San Francisco (US)
- University Hospital Regensburg (DE)
- German Cancer Research Center (DE)
- University Hospital Zurich (CH)
- Institució Catalana de Recerca i Estudis Avançats (ES)
- The University of Texas MD Anderson Cancer Center (US)
- University of Pittsburgh (US)
- Tisch Cancer Institute (US)
- Corresponding author
- Schwabe, Robert F.
- ORCID
- Nair, Ajay
- Brundu, Francesco
- Ravichandra, Aashreya
- Bhattacharjee, Sonakshi
- Matsuda, Michitaka
- Chin, LiKang
- Filliol, Aveline
- Wen, Wen
- Song, Xinhua
- Decker, Aubrianna
- Worley, Jeremy
- Yin, Deqi
- Saito, Yoshinobu
- Savage, Thomas
- Wells, Rebecca G.
- Mack, Matthias
- Zender, Lars
- Arpaia, Nicholas
- Remotti, Helen E.
- Sims, Peter
- Leblond, Anne-Laure
- Weber, Achim
- Stockwell, Brent R.
- Gaublomme, Jellert
- Llovet, Josep M.
- Kalluri, Raghu
- Michalopoulos, George K.
- Seki, Ekihiro
- Sia, Daniela
- Chen, Xin
- Califano, Andrea
- Schwabe, Robert F.
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2021-06
- Volume
- 39
- Issue
- 6
- Pages
- 866-882.e11
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC8241235
- OpenAlex
- W3157710113
- Cited by
- 416
- References
- 75
- Citations by year
- 2026: 63 · 2025: 86 · 2024: 91 · 2023: 91 · 2022: 69 · 2021: 16
- FWCI
- 62.72
- Type
- journal article
- Language
- en
- Update notices
- erratum (2021-06-14)
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 378 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- University of Regensburg Publication Server (University of Regensburg) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion)
- Funders
- Fondation pour la Recherche Medicale (SPE20170336778)
- NIH (R35CA209896, R03DK101863, 5U54CA193417, S10 OD021764, S10 OD012351, R61NS109407, R35CA197745, P01CA87497, R01CA190606, P30CA013696, R01CA190844, P30DK026743, R01CA228483, P01CA233452, R01DK085252)
- University of California, San Francisco (5U54CA193417, R35CA209896, P01CA87497, P01CA117969, R35CA197745, U01CA217858, S10 OD021764, S10 OD012351, R03DK101863, R61NS109407)
- ERC
- University of Pennsylvania
- Engineering Research Centers
- Cholangiocarcinoma Foundation
- Mayo Clinic
- American Liver Foundation
- DFG (FOR2314, SFB-TR209)
- American Gastroenterological Association
- US Department of Defense (CA150272P3)
- Topics
- Health Sciences › Medicine › Surgery › Cholangiocarcinoma and Gallbladder Cancer Studies
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Keywords
- intrahepatic cholangiocarcinoma, cancer-associated fibroblasts, hepatic stellate cells, CAF subpopulations, desmoplasia, tumor microenvironment, HAS2, hepatocyte growth factor, c-Met, type I collagen, tumor growth, tumor recurrence, prognostic signature
- MeSH terms
- Cancer-Associated Fibroblasts, Hyaluronan Synthases, Aged, Animals, Bile Duct Neoplasms, Bile Ducts, Intrahepatic, Female, Humans, Hyaluronic Acid, Male, Mice, Transgenic, Middle Aged, Hepatocyte Growth Factor, Cholangiocarcinoma, Proto-Oncogene Proteins c-met, Collagen Type I, Hepatic Stellate Cells, Tumor Microenvironment
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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