1. Promotion of cholangiocarcinoma growth by diverse cancer-associated fibroblast subpopulations.
- Author
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Affo S, Nair A, Brundu F, Ravichandra A, Bhattacharjee S, Matsuda M, Chin L, Filliol A, Wen W, Song X, Decker A, Worley J, Caviglia JM, Yu L, Yin D, Saito Y, Savage T, Wells RG, Mack M, Zender L, Arpaia N, Remotti HE, Rabadan R, Sims P, Leblond AL, Weber A, Riener MO, Stockwell BR, Gaublomme J, Llovet JM, Kalluri R, Michalopoulos GK, Seki E, Sia D, Chen X, Califano A, and Schwabe RF
- Subjects
- Aged, Animals, Bile Duct Neoplasms genetics, Bile Duct Neoplasms metabolism, Bile Ducts, Intrahepatic pathology, Cancer-Associated Fibroblasts metabolism, Cholangiocarcinoma genetics, Cholangiocarcinoma metabolism, 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, Bile Duct Neoplasms pathology, Cancer-Associated Fibroblasts pathology, Cholangiocarcinoma pathology
- 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., Competing Interests: Declaration of interests A.C. is founder, equity holder, and consultant of DarwinHealth. Columbia University is an equity holder in DarwinHealth., (Copyright © 2021 Elsevier Inc. All rights reserved.)
- Published
- 2021
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