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

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

doi:10.1016/j.celrep.2020.01.049

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

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 BarillotOlivier Delattre, Andrei Zinovyev

Research output: Contribution to journal › Article › peer-review

9 Citations (Scopus)

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.

Original language	English
Pages (from-to)	1767-1779.e6
Journal	Cell Reports
Volume	30
Issue number	6
DOIs	https://doi.org/10.1016/j.celrep.2020.01.049
Publication status	Published - Feb 11 2020
Externally published	Yes

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Aynaud, M-M., Mirabeau, O., Gruel, N., Grossetête, S., Boeva, V., Durand, S., Surdez, D., Saulnier, O., Zaïdi, S., Gribkova, S., Fouché, A., Kairov, U., Raynal, V., Tirode, F., Grünewald, T. G. P., Bohec, M., Baulande, S., Janoueix-Lerosey, I., Vert, J-P., ... Zinovyev, A. (2020). Transcriptional Programs Define Intratumoral Heterogeneity of Ewing Sarcoma at Single-Cell Resolution. Cell Reports, 30(6), 1767-1779.e6. https://doi.org/10.1016/j.celrep.2020.01.049

Transcriptional Programs Define Intratumoral Heterogeneity of Ewing Sarcoma at Single-Cell Resolution. / Aynaud, Marie-Ming; Mirabeau, Olivier; Gruel, Nadege; Grossetête, Sandrine; Boeva, Valentina; Durand, Simon; Surdez, Didier; Saulnier, Olivier; Zaïdi, Sakina; Gribkova, Svetlana; Fouché, Aziz; Kairov, Ulykbek; Raynal, Virginie; Tirode, Franck; Grünewald, Thomas G P; Bohec, Mylene; Baulande, Sylvain; Janoueix-Lerosey, Isabelle; Vert, Jean-Philippe; Barillot, Emmanuel; Delattre, Olivier; Zinovyev, Andrei.

In: Cell Reports, Vol. 30, No. 6, 11.02.2020, p. 1767-1779.e6.

Research output: Contribution to journal › Article › peer-review

Aynaud, M-M, Mirabeau, O, Gruel, N, Grossetête, S, Boeva, V, Durand, S, Surdez, D, Saulnier, O, Zaïdi, S, Gribkova, S, Fouché, A, Kairov, U, Raynal, V, Tirode, F, Grünewald, TGP, Bohec, M, Baulande, S, Janoueix-Lerosey, I, Vert, J-P, Barillot, E, Delattre, O & Zinovyev, A 2020, 'Transcriptional Programs Define Intratumoral Heterogeneity of Ewing Sarcoma at Single-Cell Resolution', Cell Reports, vol. 30, no. 6, pp. 1767-1779.e6. https://doi.org/10.1016/j.celrep.2020.01.049

Aynaud, Marie-Ming ; Mirabeau, Olivier ; Gruel, Nadege ; Grossetête, Sandrine ; Boeva, Valentina ; Durand, Simon ; Surdez, Didier ; Saulnier, Olivier ; Zaïdi, Sakina ; Gribkova, Svetlana ; Fouché, Aziz ; Kairov, Ulykbek ; Raynal, Virginie ; Tirode, Franck ; Grünewald, Thomas G P ; Bohec, Mylene ; Baulande, Sylvain ; Janoueix-Lerosey, Isabelle ; Vert, Jean-Philippe ; Barillot, Emmanuel ; Delattre, Olivier ; Zinovyev, Andrei. / Transcriptional Programs Define Intratumoral Heterogeneity of Ewing Sarcoma at Single-Cell Resolution. In: Cell Reports. 2020 ; Vol. 30, No. 6. pp. 1767-1779.e6.

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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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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

PY - 2020/2/11

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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.

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