1. Promotion of cholangiocarcinoma growth by diverse cancer-associated fibroblast subpopulations
- Author
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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, and Schwabe, Robert F
- Subjects
Genetics ,Liver Disease ,Cancer ,Digestive Diseases - (Gallbladder) ,Chronic Liver Disease and Cirrhosis ,Digestive Diseases ,Liver Cancer ,Rare Diseases ,Aetiology ,2.1 Biological and endogenous factors ,Aged ,Animals ,Bile Duct Neoplasms ,Bile Ducts ,Intrahepatic ,Cancer-Associated Fibroblasts ,Cholangiocarcinoma ,Collagen Type I ,Female ,Hepatic Stellate Cells ,Hepatocyte Growth Factor ,Humans ,Hyaluronan Synthases ,Hyaluronic Acid ,Male ,Mice ,Transgenic ,Middle Aged ,Proto-Oncogene Proteins c-met ,Tumor Microenvironment ,CellPhoneDB ,HGF ,KRAS ,YAP ,cholangiocarcinoma ,immune ,mechanosensitive ,single cell ,stiffness ,tumor microenvironment ,Neurosciences ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - 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.
- Published
- 2021