학술논문
Promotion of cholangiocarcinoma growth by diverse cancer-associated fibroblast subpopulations
Document Type
article
Author
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
Source
Cancer Cell. 39(6)
Subject
Language
Abstract
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.