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Transcriptional Programs Define Intratumoral Heterogeneity of Ewing Sarcoma at Single-Cell Resolution

Marie-Ming Aynaud
Olivier Mirabeau
Nadège Gruel
Sandrine Grossetête
Valentina Boeva
Simon Durand
Didier Surdez
Olivier Saulnier
Sakina Zaïdi
Svetlana Gribkova
Aziz Fouché
Ulykbek Kairov
Virginie Raynal
Franck Tirode
Thomas Grünewald
Mylene Bohec
Sylvain Baulande
Isabelle Janoueix-Lerosey
Jean-Philippe Vert
Emmanuel Barillot
Olivier Delattre
Andrei Zinovyev
Cell Reports, vol. 30 (2020), 1767 - 1779.e6

Abstract

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.

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