Epigenomic Reprogramming toward Mesenchymal-Epithelial Transition in Ovarian-Cancer-Associated Mesenchymal Stem Cells Drives Metastasis.
Animals
Carcinoma, Ovarian Epithelial
/ genetics
Cell Differentiation
/ genetics
Cell Line, Tumor
Cell Movement
/ genetics
Cell Proliferation
/ genetics
Enhancer of Zeste Homolog 2 Protein
/ genetics
Epigenome
/ genetics
Epigenomics
/ methods
Epithelial-Mesenchymal Transition
/ genetics
Female
Gene Expression
/ genetics
Gene Expression Regulation, Neoplastic
/ genetics
Humans
Mesenchymal Stem Cells
/ physiology
Mice
Mice, Inbred NOD
Neoplasm Metastasis
/ genetics
Ovarian Neoplasms
/ genetics
Primary Cell Culture
Signal Transduction
/ genetics
WT1 Proteins
/ genetics
EZH2
WT1
carcinoma-associated mesenchymal stem cells
epigenomic reprogramming
mesenchymal-to-epithelial transition
metastasis
ovarian cancer
tumor microenvironment
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
08 12 2020
08 12 2020
Historique:
received:
02
10
2019
revised:
26
08
2020
accepted:
11
11
2020
entrez:
9
12
2020
pubmed:
10
12
2020
medline:
9
11
2021
Statut:
ppublish
Résumé
A role for cancer cell epithelial-to-mesenchymal transition (EMT) in cancer is well established. Here, we show that, in addition to cancer cell EMT, ovarian cancer cell metastasis relies on an epigenomic mesenchymal-to-epithelial transition (MET) in host mesenchymal stem cells (MSCs). These reprogrammed MSCs, termed carcinoma-associated MSCs (CA-MSCs), acquire pro-tumorigenic functions and directly bind cancer cells to serve as a metastatic driver/chaperone. Cancer cells induce this epigenomic MET characterized by enhancer-enriched DNA hypermethylation, altered chromatin accessibility, and differential histone modifications. This phenomenon appears clinically relevant, as CA-MSC MET is highly correlated with patient survival. Mechanistically, mirroring MET observed in development, MET in CA-MSCs is mediated by WT1 and EZH2. Importantly, EZH2 inhibitors, which are clinically available, significantly inhibited CA-MSC-mediated metastasis in mouse models of ovarian cancer.
Identifiants
pubmed: 33296650
pii: S2211-1247(20)31462-5
doi: 10.1016/j.celrep.2020.108473
pmc: PMC7747301
mid: NIHMS1653542
pii:
doi:
Substances chimiques
WT1 Proteins
0
WT1 protein, human
0
EZH2 protein, human
EC 2.1.1.43
Enhancer of Zeste Homolog 2 Protein
EC 2.1.1.43
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
108473Subventions
Organisme : NCI NIH HHS
ID : K08 CA211362
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM124736
Pays : United States
Organisme : NCI NIH HHS
ID : R37 CA230748
Pays : United States
Organisme : NCI NIH HHS
ID : F32 CA225043
Pays : United States
Informations de copyright
Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Interests The authors declare no competing interests.
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