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单细胞分辨率解析尤文肉瘤肿瘤内异质性的转录程序。

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

机构信息

INSERM U830, Équipe Labellisée LNCC, SIREDO Oncology Centre, Institut Curie, 75005 Paris, France.

INSERM U830, Équipe Labellisée LNCC, SIREDO Oncology Centre, Institut Curie, 75005 Paris, France; Institut Curie, PSL Research University, Department of Translational Research, 75005 Paris, France.

出版信息

Cell Rep. 2020 Feb 11;30(6):1767-1779.e6. doi: 10.1016/j.celrep.2020.01.049.

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.

摘要

EWSR1-FLI1,尤文肉瘤(EwS)特异的嵌合性致癌基因,诱导一连串的信号事件,导致细胞转化。然而,遗传上同质的 EwS 细胞如何能够驱动转录程序的异质性仍然难以捉摸。在这里,我们将来自不同细胞类型和模型系统的单细胞 RNA 测序数据的独立成分分析与 EWSR1-FLI1 结合位点和开放染色质区域的时程映射相结合,以表征与 EWSR1-FLI1 活性相关的动态细胞过程。因此,我们定义了一个非常特异和直接的增强子驱动的 EWSR1-FLI1 程序。在 EwS 肿瘤中,细胞增殖和强烈的氧化磷酸化代谢与明确的 EWSR1-FLI1 活性范围相关。相比之下,处于中间 EWSR1-FLI1 活性以下和以上的细胞亚群的特征是缺氧增加。总体而言,我们的研究揭示了 EwS 肿瘤内肿瘤内异质性的来源。

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