Promotion of cholangiocarcinoma growth by diverse cancer-associated fibroblast subpopulations

Cancer Cell. 2021 Jun 14;39(6):866-882.e11. doi: 10.1016/j.ccell.2021.03.012. Epub 2021 Apr 29.


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.

Keywords: CellPhoneDB; HGF; KRAS; YAP; cholangiocarcinoma; immune; mechanosensitive; single cell; stiffness; tumor microenvironment.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Animals
  • Bile Duct Neoplasms / genetics
  • Bile Duct Neoplasms / metabolism
  • Bile Duct Neoplasms / pathology*
  • Bile Ducts, Intrahepatic / pathology
  • Cancer-Associated Fibroblasts / metabolism
  • Cancer-Associated Fibroblasts / pathology*
  • Cholangiocarcinoma / genetics
  • Cholangiocarcinoma / metabolism
  • Cholangiocarcinoma / pathology*
  • Collagen Type I / metabolism
  • Female
  • Hepatic Stellate Cells / cytology
  • Hepatic Stellate Cells / pathology
  • Hepatocyte Growth Factor / metabolism
  • Humans
  • Hyaluronan Synthases / genetics
  • Hyaluronan Synthases / metabolism
  • Hyaluronic Acid / metabolism
  • Male
  • Mice, Transgenic
  • Middle Aged
  • Proto-Oncogene Proteins c-met / metabolism
  • Tumor Microenvironment


  • Collagen Type I
  • HGF protein, human
  • Hepatocyte Growth Factor
  • Hyaluronic Acid
  • HAS2 protein, human
  • Hyaluronan Synthases
  • MET protein, human
  • Proto-Oncogene Proteins c-met