TY - JOUR
T1 - Transcriptional Programs Define Intratumoral Heterogeneity of Ewing Sarcoma at Single-Cell Resolution
AU - Aynaud, Marie-Ming
AU - Mirabeau, Olivier
AU - Gruel, Nadege
AU - Grossetête, Sandrine
AU - Boeva, Valentina
AU - Durand, Simon
AU - Surdez, Didier
AU - Saulnier, Olivier
AU - Zaïdi, Sakina
AU - Gribkova, Svetlana
AU - Fouché, Aziz
AU - Kairov, Ulykbek
AU - Raynal, Virginie
AU - Tirode, Franck
AU - Grünewald, Thomas G P
AU - Bohec, Mylene
AU - Baulande, Sylvain
AU - Janoueix-Lerosey, Isabelle
AU - Vert, Jean-Philippe
AU - Barillot, Emmanuel
AU - Delattre, Olivier
AU - Zinovyev, Andrei
N1 - Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.
PY - 2020/2/11
Y1 - 2020/2/11
N2 - 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.
AB - 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.
U2 - 10.1016/j.celrep.2020.01.049
DO - 10.1016/j.celrep.2020.01.049
M3 - Article
C2 - 32049009
VL - 30
SP - 1767-1779.e6
JO - Cell Reports
JF - Cell Reports
SN - 2211-1247
IS - 6
ER -