Promotion of cholangiocarcinoma growth by diverse cancer-associated fibroblast subpopulations.
Aged
Animals
Bile Duct Neoplasms
/ genetics
Bile Ducts, Intrahepatic
/ pathology
Cancer-Associated Fibroblasts
/ metabolism
Cholangiocarcinoma
/ genetics
Collagen Type I
/ metabolism
Female
Hepatic Stellate Cells
/ cytology
Hepatocyte Growth Factor
/ metabolism
Humans
Hyaluronan Synthases
/ genetics
Hyaluronic Acid
/ metabolism
Male
Mice, Transgenic
Middle Aged
Proto-Oncogene Proteins c-met
/ metabolism
Tumor Microenvironment
CellPhoneDB
HGF
KRAS
YAP
cholangiocarcinoma
immune
mechanosensitive
single cell
stiffness
tumor microenvironment
Journal
Cancer cell
ISSN: 1878-3686
Titre abrégé: Cancer Cell
Pays: United States
ID NLM: 101130617
Informations de publication
Date de publication:
14 06 2021
14 06 2021
Historique:
received:
30
07
2020
revised:
26
01
2021
accepted:
29
03
2021
pubmed:
1
5
2021
medline:
18
12
2021
entrez:
30
4
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33930309
pii: S1535-6108(21)00170-7
doi: 10.1016/j.ccell.2021.03.012
pmc: PMC8241235
mid: NIHMS1695680
pii:
doi:
Substances chimiques
Collagen Type I
0
HGF protein, human
0
Hepatocyte Growth Factor
67256-21-7
Hyaluronic Acid
9004-61-9
HAS2 protein, human
EC 2.4.1.212
Hyaluronan Synthases
EC 2.4.1.212
MET protein, human
EC 2.7.10.1
Proto-Oncogene Proteins c-met
EC 2.7.10.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
866-882.e11Subventions
Organisme : NCI NIH HHS
ID : R35 CA209896
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK026743
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA117969
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK085252
Pays : United States
Organisme : NCI NIH HHS
ID : U54 CA193417
Pays : United States
Organisme : NIH HHS
ID : S10 OD012351
Pays : United States
Organisme : NIH HHS
ID : S10 OD021764
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA228483
Pays : United States
Organisme : NCI NIH HHS
ID : R35 CA197745
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA190606
Pays : United States
Organisme : NIDDK NIH HHS
ID : R03 DK101863
Pays : United States
Organisme : NIEHS NIH HHS
ID : P30 ES013508
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA087497
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA190844
Pays : United States
Organisme : NINDS NIH HHS
ID : R61 NS109407
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA013696
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA233452
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA217858
Pays : United States
Commentaires et corrections
Type : ErratumIn
Informations de copyright
Copyright © 2021 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests A.C. is founder, equity holder, and consultant of DarwinHealth. Columbia University is an equity holder in DarwinHealth.
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