Transcriptional Programs Define Intratumoral Heterogeneity of Ewing Sarcoma at Single-Cell Resolution.
EWSR1-FLI1
Ewing sarcoma
Independent Component Analysis
intratumor heterogeneity
patient-derived xenografts
single-cell RNA-sequencing
time series
transcriptomics
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
11 02 2020
11 02 2020
Historique:
received:
19
04
2019
revised:
07
10
2019
accepted:
15
01
2020
entrez:
13
2
2020
pubmed:
13
2
2020
medline:
9
3
2021
Statut:
ppublish
Résumé
EWSR1-FLI1, the chimeric oncogene specific for Ewing sarcoma (EwS), induces a cascade of signaling events leading to cell transformation. However, it remains elusive how genetically homogeneous EwS cells can drive the heterogeneity of transcriptional programs. Here, we combine independent component analysis of single-cell RNA sequencing data from diverse cell types and model systems with time-resolved mapping of EWSR1-FLI1 binding sites and of open chromatin regions to characterize dynamic cellular processes associated with EWSR1-FLI1 activity. We thus define an exquisitely specific and direct enhancer-driven EWSR1-FLI1 program. In EwS tumors, cell proliferation and strong oxidative phosphorylation metabolism are associated with a well-defined range of EWSR1-FLI1 activity. In contrast, a subpopulation of cells from below and above the intermediary EWSR1-FLI1 activity is characterized by increased hypoxia. Overall, our study reveals sources of intratumoral heterogeneity within EwS tumors.
Identifiants
pubmed: 32049009
pii: S2211-1247(20)30074-7
doi: 10.1016/j.celrep.2020.01.049
pii:
doi:
Substances chimiques
EWSR1 protein, human
0
RNA-Binding Protein EWS
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1767-1779.e6Informations de copyright
Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Interests The authors declare no competing interests.