PRC2-Mediated Transcriptomic Alterations at the Embryonic Stage Govern Tumorigenesis and Clinical Outcome in MYCN-Driven Neuroblastoma
PRC2-Mediated Transcriptomic Alterations at the Embryonic Stage Govern Tumorigenesis and Clinical Outcome in MYCN-Driven Neuroblastoma
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DOI：
10.1158/0008-5472.can-16-3144
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发表时间：
2017-10-01
期刊：
影响因子：
11.2
通讯作者：
Kadomatsu, Kenji
中科院分区：
文献类型：
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作者：
Tsubota, Shoma;Kishida, Satoshi;Kadomatsu, Kenji
神经母细胞瘤等儿科癌症被认为与胚胎发育失调有关。然而，很难确定触发肿瘤发生的关键事件，并将它们与正常发育区分开来。在这项研究中，我们报告了一种从神经母细胞瘤的临床前模型TH-MYCN小鼠中培养早期肿瘤细胞的球形培养方法的建立。利用这种方法，我们发现早在胚胎发育的E13.5天就有明显的致瘤细胞，当时MYC和PRC2转录本发生了显著的变化。EZH2是PRC2的重要组成部分，在胚胎和出生后的肿瘤组织中表达，并与N-MYC密切相关，我们观察到H3K27me3在PRC2靶基因上增加。抑制PRC2抑制体外球体的形成，降低其靶基因，并抑制原位肿瘤生长。在临床标本中，MYC和PRC2靶基因的表达与预后密切相关。总而言之，我们的发现强调了胚胎发生过程中PRC2介导的转录调控是神经母细胞瘤发展和临床结局的关键步骤。(C)2017年AACR。
Pediatric cancers such as neuroblastoma are thought to involve a dysregulation of embryonic development. However, it has been difficult to identify the critical events that trigger tumorigenesis and differentiate them from normal development. In this study, we report the establishment of a spheroid culture method that enriches early-stage tumor cells from TH-MYCN mice, a preclinical model of neuroblastoma. Using this method, we found that tumorigenic cells were evident as early as day E13.5 during embryo development, when the MYC and PRC2 transcriptomes were significantly altered. Ezh2, an essential component of PRC2, was expressed in embryonic and postnatal tumor lesions and physically associated with N-MYC and we observed that H3K27me3 was increased at PRC2 target genes. PRC2 inhibition suppressed in vitro sphere formation, derepressed its target genes, and suppressed in situ tumor growth. In clinical specimens, expression of MYC and PRC2 target genes correlated strongly and predicted survival outcomes. Together, our findings highlighted PRC2-mediated transcriptional control during embryogenesis as a critical step in the development and clinical outcome of neuroblastoma. (C) 2017 AACR.