@article{19dc85e0244f4dca89dda665e334dd77,
title = "Promotion of cholangiocarcinoma growth by diverse cancer-associated fibroblast subpopulations",
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.",
keywords = "CellPhoneDB, HGF, KRAS, YAP, cholangiocarcinoma, immune, mechanosensitive, single cell, stiffness, tumor microenvironment",
author = "Silvia Affo and Ajay Nair and Francesco Brundu and Aashreya Ravichandra and Sonakshi Bhattacharjee and Michitaka Matsuda and Chin, {Li Kang} and Aveline Filliol and Wen Wen and Xinhua Song and Aubrianna Decker and Jeremy Worley and Caviglia, {Jorge Matias} and Lexing Yu and Deqi Yin and Yoshinobu Saito and Thomas Savage and Wells, {Rebecca G.} and Matthias Mack and Lars Zender and Nicholas Arpaia and Remotti, {Helen E.} and Raul Rabadan and Peter Sims and Leblond, {Anne Laure} and Achim Weber and Riener, {Marc Oliver} and Stockwell, {Brent R.} and Jellert Gaublomme and Llovet, {Josep M.} and Raghu Kalluri and Michalopoulos, {George K.} and Ekihiro Seki and Daniela Sia and Xin Chen and Andrea Califano and Schwabe, {Robert F.}",
note = "Funding Information: This work was supported by: NIH R01CA228483 (R.F.S., X.C.); R01CA190844 (R.F.S.); P30CA013696 (Columbia University Cancer Center); R01DK085252 , P01CA233452 (E.S.); R01CA190606 (X.C.); P30DK026743 (UCSF Liver Center); 5U54CA193417 (R.W.); R35CA197745. S10 OD012351, S10 OD021764, U01CA217858 (A.C.); P01CA117969, Project 3 (R.K.); R03DK101863 (J.M.C); P01CA87497 , R35CA209896 , R61NS109407 (B.R.S); US Department of Defense grant CA150272P3 (J.M.L.); Swiss National Science Foundation SNF310030_146940 (A.W., A.L.); Deutsche Forschungsgemeinschaft FOR2314 , SFB-TR209 , Gottfried Wilhelm Leibniz Program , and ERC {\textquoteleft}CholangioConcept{\textquoteright} (L.Z.). S.A. was funded by an American Liver Foundation Postdoctoral Research Fellowship Award, a Cholangiocarcinoma Foundation 's Innovation Award, and a Research Scholar Award from the American Gastroenterological Association ; S.B. by Deutsche Forschungemeinschaft grant GZ:BH 155/1-1 ; A.F. by Recherche M{\'e}dicale 's postdoctoral fellowship SPE20170336778 and an American Liver Foundation 's Postdoctoral Research Award. We thank Drs. Liang Zhao and Ellen Pure (University of Pennsylvania) for CD44 floxed mice; Susanne Dettwiler, Fabiola Prutek, Andr{\'e} Fitsche, Christine Mittmann, and Marcel Gl{\"o}nkler (University of Z{\"u}rich) for TMA sections and IHC; Dr. Gregory Gores (Mayo Clinic, Rochester, MN) for CCA cell lines; and Drs. Timothy Wang and Kenneth Olive (Columbia University) for critical reading. Funding Information: This work was supported by: NIH R01CA228483 (R.F.S. X.C.); R01CA190844 (R.F.S.); P30CA013696 (Columbia University Cancer Center); R01DK085252, P01CA233452 (E.S.); R01CA190606 (X.C.); P30DK026743 (UCSF Liver Center); 5U54CA193417 (R.W.); R35CA197745. S10 OD012351, S10 OD021764, U01CA217858 (A.C.); P01CA117969, Project 3 (R.K.); R03DK101863 (J.M.C); P01CA87497, R35CA209896, R61NS109407 (B.R.S); US Department of Defense grant CA150272P3 (J.M.L.); Swiss National Science Foundation SNF310030_146940 (A.W. A.L.); Deutsche Forschungsgemeinschaft FOR2314, SFB-TR209, Gottfried Wilhelm Leibniz Program, and ERC ?CholangioConcept? (L.Z.). S.A. was funded by an American Liver Foundation Postdoctoral Research Fellowship Award, a Cholangiocarcinoma Foundation's Innovation Award, and a Research Scholar Award from the American Gastroenterological Association; S.B. by Deutsche Forschungemeinschaft grant GZ:BH 155/1-1; A.F. by Recherche M?dicale's postdoctoral fellowship SPE20170336778 and an American Liver Foundation's Postdoctoral Research Award. We thank Drs. Liang Zhao and Ellen Pure (University of Pennsylvania) for CD44 floxed mice; Susanne Dettwiler, Fabiola Prutek, Andr? Fitsche, Christine Mittmann, and Marcel Gl?nkler (University of Z?rich) for TMA sections and IHC; Dr. Gregory Gores (Mayo Clinic, Rochester, MN) for CCA cell lines; and Drs. Timothy Wang and Kenneth Olive (Columbia University) for critical reading. Conceptualization, R.F.S. and S.A.; Methodology, R.F.S. S.A. X.C. R.G.W. A.N. F.B. and D.S.; Experimentation, S.A. A.N. F.B. A.R. S.B. T.S. M. Matsuda. L.C. A.F. W.W. Y.S. J.W. D.Y. X.S. A.D. J.M.C. L.Z. H.E.R. A.L.L. and D.S.; Writing, R.F.S. and S.A.; Funding acquisition, R.F.S. X.C. and S.A.; Resources, R.F.S. N.A. A.W. M.-O.R. M. Mack, B.R.S. J.G. G.K.M. L.Y. J.M.L. D.S. E.S. R.R. P.S. X.C. and A.C.; Supervision, R.F.S. A.C. is founder, equity holder, and consultant of DarwinHealth. Columbia University is an equity holder in DarwinHealth. Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",
year = "2021",
month = jun,
day = "14",
doi = "10.1016/j.ccell.2021.03.012",
language = "English",
volume = "39",
pages = "866--882.e11",
journal = "Cancer Cell",
issn = "1535-6108",
publisher = "Cell Press",
number = "6",
}