Cell reports · 2020
Transcriptional Programs Define Intratumoral Heterogeneity of Ewing Sarcoma at Single-Cell Resolution.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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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
Аннотация
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.