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

Marie-Ming Aynaud (1) , Olivier Mirabeau (1) , Nadege Gruel (1) , Sandrine Grossetête (1) , Valentina Boeva (2, 3, 4) , Simon Durand (1) , Didier Surdez (1) , Olivier Saulnier (1) , Sakina Zaïdi (1) , Svetlana Gribkova (5) , Aziz Fouché (6) , Ulykbek Kairov (7) , Virginie Raynal (1) , Franck Tirode (8) , Thomas G.P. Grünewald (1) , Mylene Bohec (9) , Sylvain Baulande (9) , Isabelle Janoueix-Lerosey (1) , Jean-Philippe Vert (10, 4) , Emmanuel Barillot (5) , Olivier Delattre (1) , Andrei Zinovyev (5, 4)

1 U830 - Unité de génétique et biologie des cancers
2 D-INFK - Department of Computer Science [ETH Zürich]
3 IC UM3 (UMR 8104 / U1016) - Institut Cochin
4 CBIO - Centre de Bioinformatique
5 Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe
6 ENS Paris Saclay - Ecole Normale Supérieure Paris-Saclay
7 Nazarbayev University [Kazakhstan]
8 UNICANCER/CRCL - Centre de Recherche en Cancérologie de Lyon
9 Institut Curie [Paris]
10 Google Brain, Paris

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.

Mots clés: EWSR1-FLI1; Ewing sarcoma; Independent Component Analysis; intratumor heterogeneity; patient-derived xenografts; single-cell RNA-sequencing; time series; transcriptomics

Domaines: Bio-Informatique, Biologie Systémique [q-bio.QM]; Cancer

Marie-Ming Aynaud, Olivier Mirabeau, Nadege Gruel, Sandrine Grossetête, Valentina Boeva, et al.. Transcriptional Programs Define Intratumoral Heterogeneity of Ewing Sarcoma at Single-Cell Resolution. Cell Reports, 2020, 30 (6), pp.1767-1779.e6. ⟨10.1016/j.celrep.2020.01.049⟩. ⟨hal-02972224⟩