Promotion of cholangiocarcinoma growth by diverse cancer-associated fibroblast subpopulations

Silvia Affo, Ajay Nair, Francesco Brundu, Aashreya Ravichandra, Sonakshi Bhattacharjee, Michitaka Matsuda, Li Kang Chin, Aveline Filliol, Wen Wen, Xinhua Song, Aubrianna Decker, Jeremy Worley, Jorge Matias Caviglia, Lexing Yu, Deqi Yin, Yoshinobu Saito, Thomas Savage, Rebecca G. Wells, Matthias Mack, Lars ZenderNicholas Arpaia, Helen E. Remotti, Raul Rabadan, Peter Sims, Anne Laure Leblond, Achim Weber, Marc Oliver Riener, Brent R. Stockwell, Jellert Gaublomme, Josep M. Llovet, Raghu Kalluri, George K. Michalopoulos, Ekihiro Seki, Daniela Sia, Xin Chen, Andrea Califano, Robert F. Schwabe

Research output: Contribution to journalArticlepeer-review

106 Scopus citations


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.

Original languageEnglish
Pages (from-to)866-882.e11
JournalCancer Cell
Issue number6
StatePublished - 14 Jun 2021


  • CellPhoneDB
  • HGF
  • KRAS
  • YAP
  • cholangiocarcinoma
  • immune
  • mechanosensitive
  • single cell
  • stiffness
  • tumor microenvironment


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