Transcriptional activation of RCOR2 as a novel oncogenic mechanism in supratentorial ependymoma

RCOR2的转录激活作为幕上室管膜瘤的新型致癌机制

• 批准号: 10762312
• 负责人: Lukas Chavez
• 金额: $ 53.63万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-07 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10762312
• 关键词: Transcriptional; activation; RCOR2; novel; oncogenic

PROJECT SUMMARY Brain and other tumors of the central-nervous system (CNS) are the most common cancers in children aged 0-14 years in the USA. Ependymoma (EPN) is the third most common pediatric brain tumor and a leading cause of death in childhood cancer patients. The two most common and most aggressive molecular subgroups of ependymoma are the supratentorial ZFTA/C11orf95-fusion associated group (ST-ZFTA-EPN, formerly ST-RELA-EPN) and the posterior fossa ependymoma group A (PF-A-EPN). Although the molecular mechanisms underlying these diseases have recently been uncovered, they remain difficult to target and innovative therapeutic approaches are urgently needed. The overall objective of this proposal is to identify molecular mechanisms underlying aberrant expression of genes that are essential for tumorigenesis and contribute to the poor survival of ST-ZFTA-EPN patients. To approach this objective, we have analyzed the 3D conformation of primary ST-ZFTA-EPN tumors and cell lines using genome-wide chromosome conformation capture (Hi-C). As a result, we observe the formation of new topologically associating domains (‘neo-TADs’) induced by structural variants (SVs) in all ST-ZFTA-EPN tumors, placing the REST Corepressor 2 (RCOR2) gene into a new regulatory environment. By evaluating Affymetrix gene expression array data across ependymoma groups, we found that RCOR2 transcription is significantly upregulated in ST-ZFTA-EPN relative to other ependymoma groups. Through inhibition experiments, we validated that RCOR2 is highly essential for the survival of a patient-derived ST-ZFTA-EPN cell line in a disease subtype-specific manner. Based on these preliminary results, we now hypothesize that transcriptional activation of RCOR2 is induced by structural variants and the formation of neo-TADs, which contributes to tumorigenesis in ST-ZFTA-EPN patients. The central hypothesis will be tested by pursuing to answer two specific aims: First, we aim to functionally validate transcriptional activation of RCOR2 by structural variants and the formation of neo-TADs (Specific Aim 1). Second, we aim to dissect the role of RCOR2 in tumorigenesis of supratentorial ZFTA- RELA fusion associated ependymomas (Specific Aim 2). The rationale for this project is that experiments studying the function of RCOR2 in patient-derived models of ST-ZFTA-EPN tumors are likely to provide a strong scientific framework in which basic mechanisms of ependymoma tumorigenesis and new therapeutic opportunities can be identified. The research proposed in this application is innovative, in the applicant’s opinion, because it interrogates a novel molecular mechanism of transcriptional RCOR2 activation in recently derived faithful models of ST-ZFTA-EPN. The proposed research is significant, because it is expected to provide new therapeutic opportunities for a pediatric brain tumor type that is a leading cause of death in childhood cancer patients. Ultimately, our studies have the potential to functionally validate RCOR2 and its associated protein complexes as drivers of ST-ZFTA-EPN tumors and as a novel therapeutic vulnerability in this devastating disease.

项目摘要 脑肿瘤和中枢神经系统（CNS）的其他肿瘤是年龄较大的儿童中最常见的癌症。 0-14年在美国。室管膜瘤（Ependymoma，EPN）是第三常见的小儿脑肿瘤， 儿童癌症患者的死亡原因。两种最常见和最具攻击性的分子 室管膜瘤的亚组是幕上ZFTA/C11 orf 95融合相关组（ST-ZFTA-EPN， 前ST-RELA-EPN）和后颅窝室管膜瘤A组（PF-A-EPN）。虽然分子 这些疾病的潜在机制最近被发现，但仍然难以靶向 迫切需要创新的治疗方法。本建议的总体目标是 确定肿瘤发生所必需的基因异常表达的分子机制 并导致ST-ZFTA-EPN患者生存率低。为了实现这一目标，我们分析了 原发性ST-ZFTA-EPN肿瘤及细胞系全基因组染色体三维构象研究 构象捕获（Hi-C）。结果，我们观察到新的拓扑关联域的形成 在所有ST-ZFTA-EPN肿瘤中由结构变体（SV）诱导的新TADs，将REST辅阻遏物2 （RCOR 2）基因进入新的调控环境。通过评估Affymbox基因表达阵列数据， 在室管膜瘤组中，我们发现RCOR 2转录在ST-ZFTA-EPN中显著上调， 相对于其他室管膜瘤组。通过抑制实验，我们验证了RCOR 2是一种高度 以疾病亚型特异性方式对患者来源的ST-ZFTA-EPN细胞系的存活至关重要。 基于这些初步的结果，我们现在假设RCOR 2的转录激活被诱导， 通过结构变异和新TADs的形成，这有助于ST-ZFTA-EPN的肿瘤发生 患者中心假设将通过追求回答两个具体目标来检验：首先，我们的目标是 通过结构变体和neo-TADs的形成在功能上验证RCOR 2的转录激活 （具体目标1）。其次，我们的目的是剖析RCOR 2在幕上ZFTA肿瘤发生中的作用， RELA融合相关室管膜瘤（特定目标2）。这个项目的基本原理是， 在ST-ZFTA-EPN肿瘤的患者来源模型中研究RCOR 2的功能可能会提供一个 室管膜瘤发生的基本机制和新的治疗方法 机会是可以识别的。本申请中提出的研究是创新的，在申请人的 因为它询问了一种新的转录RCOR 2激活的分子机制， 最近导出的ST-ZFTA-EPN的忠实模型。这项研究意义重大，因为它 预计将为儿童脑肿瘤类型提供新的治疗机会，这是导致儿童脑肿瘤的主要原因。 儿童癌症患者的死亡率。最终，我们的研究有可能在功能上验证RCOR 2 及其相关蛋白复合物作为ST-ZFTA-EPN肿瘤的驱动剂和作为新的治疗剂 在这种毁灭性疾病中的脆弱性。