Promotion of cholangiocarcinoma growth by diverse cancer-associated fibroblast subpopulations

• Published in: Cancer cell Vol. 39; no. 6; pp. 866 - 882.e11
• Main Authors: Affo, Silvia, Nair, Ajay, Brundu, Francesco, Ravichandra, Aashreya, Bhattacharjee, Sonakshi, Matsuda, Michitaka, Chin, LiKang, Filliol, Aveline, Wen, Wen, Song, Xinhua, Decker, Aubrianna, Worley, Jeremy, Caviglia, Jorge Matias, Yu, Lexing, Yin, Deqi, Saito, Yoshinobu, Savage, Thomas, Wells, Rebecca G., Mack, Matthias, Zender, Lars, Arpaia, Nicholas, Remotti, Helen E., Rabadan, Raul, Sims, Peter, Leblond, Anne-Laure, Weber, Achim, Riener, Marc-Oliver, Stockwell, Brent R., Gaublomme, Jellert, Llovet, Josep M., Kalluri, Raghu, Michalopoulos, George K., Seki, Ekihiro, Sia, Daniela, Chen, Xin, Califano, Andrea, Schwabe, Robert F.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 14.06.2021
• Subjects: 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; CellPhoneDB; cholangiocarcinoma; Cholangiocarcinoma - genetics; Cholangiocarcinoma - metabolism; Cholangiocarcinoma - pathology; Collagen Type I - metabolism; Female; Hepatic Stellate Cells - cytology; Hepatic Stellate Cells - pathology; Hepatocyte Growth Factor - metabolism; HGF; Humans; Hyaluronan Synthases - genetics; Hyaluronan Synthases - metabolism; Hyaluronic Acid - metabolism; immune; KRAS; Male; mechanosensitive; Mice, Transgenic; Middle Aged; Proto-Oncogene Proteins c-met - metabolism; single cell; stiffness; Tumor Microenvironment; YAP; single cell; immune; mechanosensitive; CellPhoneDB; HGF; YAP; KRAS; tumor microenvironment; stiffness; cholangiocarcinoma
• ISSN: 1535-6108; 1878-3686; 1878-3686
• DOI: 10.1016/j.ccell.2021.03.012

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. [Display omitted] •The majority of CAF in ICC are derived from hepatic stellate cells•Inflammatory CAF promote ICC through HGF and its receptor MET•myCAF promote ICC through Has2/hyaluronic acid•CAF-derived type I collagen contributes to stiffness but does not promote ICC growth Intrahepatic cholangiocarcinoma (ICC) is an extraordinarily stiff liver tumor due to abundant scar-forming cancer-associated fibroblasts (CAF). Here, Affo et al. determine the origin and functions of CAF, and uncover distinct CAF subsets, promoting ICC growth via different therapeutically targetable mediators. Thus, CAF and their mediators may serve as therapeutic targets for ICC.