1. Transcriptional Programs Define Intratumoral Heterogeneity of Ewing Sarcoma at Single-Cell Resolution
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Marie-Ming Aynaud, Olivier Mirabeau, Nadege Gruel, Sandrine Grossetête, Valentina Boeva, Simon Durand, Didier Surdez, Olivier Saulnier, Sakina Zaïdi, Svetlana Gribkova, Aziz Fouché, Ulykbek Kairov, Virginie Raynal, Franck Tirode, Thomas G.P. Grünewald, Mylene Bohec, Sylvain Baulande, Isabelle Janoueix-Lerosey, Jean-Philippe Vert, Emmanuel Barillot, Olivier Delattre, Andrei Zinovyev, Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Computer Science [ETH Zürich] (D-INFK), Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Centre de Bioinformatique (CBIO), Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Ecole Normale Supérieure Paris-Saclay (ENS Paris Saclay), Nazarbayev University [Kazakhstan], Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Curie [Paris], Google Brain, Paris, ITMO Cancer SysBio program (MOSAIC project, Nb bio 2014-2), Ministry of Education and Science of the Republic of Kazakhstan, grant 'Pan-cancer deconvolution of omics data using Independent Component Analysis' (IRN: AP05135430), German Cancer Aid (DKH-70112257), ANR-19-P3IA-0001,PRAIRIE,PaRis Artificial Intelligence Research InstitutE(2019), ANR-10-EQPX-0003,ICGex,Equipement de biologie intégrative du cancer pour une médecine personnalisée(2010), European Project: 826121,iPaediatricCurie, European Project: ERA-649,PRAVABES, European Project: 602856,EC:FP7:HEALTH,FP7-HEALTH-2013-INNOVATION-1,EEC(2013), Zinovyev, Andrei, PaRis Artificial Intelligence Research InstitutE - - PRAIRIE2019 - ANR-19-P3IA-0001 - P3IA - VALID, Equipements d'excellence - Equipement de biologie intégrative du cancer pour une médecine personnalisée - - ICGex2010 - ANR-10-EQPX-0003 - EQPX - VALID, European Union’s Horizon 2020 program (grant No. 826121, iPC project) - iPaediatricCurie - 826121 - INCOMING, NET TRANSCAN JTC-2011 - PRAVABES - ERA-649 - INCOMING, EURO EWING Consortium – International Clinical Trials to Improve Survival from Ewing Sarcoma - EEC - - EC:FP7:HEALTH2013-10-01 - 2018-09-30 - 602856 - VALID, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), MINES ParisTech - École nationale supérieure des mines de Paris, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)
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[SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM] ,Transcription, Genetic ,EWSR1-FLI1 ,fungi ,intratumor heterogeneity ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Sarcoma, Ewing ,Independent Component Analysis ,[SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM] ,Gene Expression Regulation, Neoplastic ,transcriptomics ,lcsh:Biology (General) ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,Cell Line, Tumor ,Humans ,single-cell RNA-sequencing ,RNA-Binding Protein EWS ,patient-derived xenografts ,time series ,lcsh:QH301-705.5 ,Ewing sarcoma ,Signal Transduction - 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., Cell Reports, 30 (6), ISSN:2666-3864, ISSN:2211-1247
- Published
- 2020
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