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.

项目概要 脑肿瘤和中枢神经系统 (CNS) 的其他肿瘤是儿童中最常见的癌症 0-14 岁在美国。室管膜瘤 (EPN) 是第三种最常见的儿童脑肿瘤，也是一种主要的 儿童癌症患者的死亡原因。两种最常见、最具攻击性的分子 室管膜瘤的亚组是幕上 ZFTA/C11orf95 融合相关组（ST-ZFTA-EPN， 以前称为 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已被发现，但仍然难以针对它们 迫切需要创新的治疗方法。该提案的总体目标是 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 患者的生存率较差。为了实现这一目标，我们分析了 使用全基因组染色体显示原发性 ST-ZFTA-EPN 肿瘤和细胞系的 3D 构象 构象捕获（Hi-C）。结果，我们观察到新的拓扑关联域的形成 （“neo-TAD”）由所有 ST-ZFTA-EPN 肿瘤中的结构变异 (SV) 诱导，将 REST 辅阻遏物 2 （RCOR2）基因进入新的调控环境。通过评估 Affymetrix 基因表达阵列数据 室管膜瘤组中，我们发现 ST-ZFTA-EPN 中 RCOR2 转录显着上调 相对于其他室管膜瘤组。通过抑制实验，我们验证了 RCOR2 具有高度 对于患者来源的 ST-ZFTA-EPN 细胞系以疾病亚型特异性方式的生存至关重要。 基于这些初步结果，我们现在假设 RCOR2 的转录激活是被诱导的 通过结构变异和新 TAD 的形成，这有助于 ST-ZFTA-EPN 的肿瘤发生 患者。将通过追求回答两个具体目标来检验中心假设：首先，我们的目标是 通过结构变异和 neo-TAD 的形成来功能验证 RCOR2 的转录激活 （具体目标1）。其次，我们的目的是剖析 RCOR2 在幕上 ZFTA-肿瘤发生中的作用 RELA 融合相关室管膜瘤（具体目标 2）。该项目的基本原理是实验 研究 RCOR2 在患者来源的 ST-ZFTA-EPN 肿瘤模型中的功能可能会提供一个新的思路。 强有力的科学框架，其中室管膜瘤肿瘤发生的基本机制和新的治疗方法 可以识别机会。本申请提出的研究具有创新性，在申请人的 意见，因为它质疑转录 RCOR2 激活的新分子机制 最近导出了 ST-ZFTA-EPN 的忠实模型。拟议的研究意义重大，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。最终，我们的研究有可能在功能上验证 RCOR2 及其相关蛋白复合物作为 ST-ZFTA-EPN 肿瘤的驱动因素和新型治疗方法 在这种毁灭性疾病中的脆弱性。