Transcriptional activation of LAMC1 as a resistance mechanism in recurrent PFA Ependymoma

LAMC1 的转录激活作为复发性 PFA 室管膜瘤的耐药机制

• 批准号: 10762310
• 负责人: Lukas Chavez
• 金额: $ 19.59万
• 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 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10762310
• 关键词: Transcriptional; activation; LAMC1; resistance; mechanism

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 most common and aggressive subgroup, posterior fossa ependymoma group A (PFA), occurs mainly in young children and frequently leads to recurrences. Despite extensive DNA sequencing studies, the only molecular marker associated with particularly poor survival is gain of the chromosome arm 1q. The overall objective of this proposal is to identify the molecular mechanisms that cause the poor survival of 1q+ PFA EPN patients. To approach this objective, we have analyzed the 3D conformation of 1q+ PFA EPN tumor genomes using HiC. As a result, we identify complex inter-chromosomal structural variants (SVs) that result in the formation of new topologically associated domains (‘neo-TADs’) leading to transcriptional activation of LAMC1. Based on these results, we now hypothesize that the transcriptional activation of LAMC1 by the formation of SV-induced neo-TADs is a common resistance mechanism in recurrent 1q+ PFA EPN tumors. Thus, strategies that target LAMC1 may reveal new vulnerabilities and overcome resistance to therapy in the treatment of PFA EPN relapse patients. The rationale for this project is that resolving SVs in a larger cohort of available PFA EPN relapse samples using HiC and functional inhibition experiments against LAMC1 in relapse PFA EPN models are likely to provide a strong scientific framework in which basic mechanisms of epigenetically linked activation of proliferation and new therapeutic opportunities can be identified. The central hypothesis will be tested by pursuing to answer two specific aims: First, we aim to determine the frequency of SVs in a larger cohort of 1q+ PFA ependymomas and their impact on regulatory domains (Aim 1). Second, we aim to determine the therapeutic potential of targeting LAMC1 in patient-derived models of relapse PFA ependymomas (Aim 2). Ultimately, our studies have the potential to improve our understanding of the epigenetic regulation that drives the acquisition of stemness and resistance to therapy and to advance the treatment of PFA EPN patients. The research proposed in this application is innovative, in the applicant’s opinion, because it interrogates a new molecular mechanism of transcriptional LAMC1 activation in recently derived faithful models of PFA 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 improve our understanding of the epigenetic regulation that drives the acquisition of stemness and to advance the treatment of diseases.

脑肿瘤和其他中枢神经系统(CNS)肿瘤是0岁以下儿童最常见的癌症。 在美国待了14年。室管膜瘤(EPN)是儿科第三常见的脑肿瘤，也是引起脑室管膜瘤的主要原因。 儿童癌症患者的死亡风险。最常见和最具侵袭性的亚群是后颅窝 室管膜瘤A组(PFA)，主要发生在幼儿，常导致复发。尽管 广泛的DNA测序研究表明，与存活率特别低相关的唯一分子标记是获得性 染色体臂1q。这项提议的总体目标是确定 导致1Q+PFA EPN患者存活率低。为了达到这一目标，我们分析了3D HIC法检测1q+PFA EPN肿瘤基因组构象因此，我们确定了复杂的染色体间 结构变体(SVS)，导致形成新的拓扑相关结构域(‘neo-TADS’) 涉及LAMC1的转录激活。基于这些结果，我们现在假设转录 通过SV诱导的neo-TADS的形成激活LAMC1是复发患者常见的耐药机制 1Q+PFA EPN肿瘤。因此，以LAMC1为目标的策略可能会发现新的漏洞并克服 PFA EPN复发患者治疗中的抗药性。这个项目的基本原理是解决 使用HIC和功能抑制实验在较大的可用PFA EPN复发样本队列中的SVS 针对复发的LAMC1，PFA EPN模型可能提供一个强有力的科学框架，在其中 表观遗传相关的增殖激活和新的治疗机会的机制可以 确认身份。核心假设将通过寻求回答两个具体目标来检验：第一，我们的目标是 确定在1Q+PFA室管膜瘤的较大队列中SVS的频率及其对调节的影响 领域(目标1)。第二，我们的目标是确定靶向LAMC1在患者来源的治疗中的潜力 复发性PFA室管膜瘤模型(目标2)。归根结底，我们的研究有可能提高我们的 对表观遗传调控的理解，表观遗传调控推动了茎的获得和对治疗和 目的：提高PFA EPN患者的治疗水平。本申请中提出的研究是创新的，在 申请人的意见，因为它询问了一种新的转录LAMC1激活的分子机制 最近推出了PFA EPN的忠实模型。这项拟议的研究意义重大，因为预计它将 为儿童脑肿瘤类型提供新的治疗机会，这种肿瘤是儿童死亡的主要原因 癌症患者。最终，我们的研究有可能提高我们对表观遗传学的理解 促进获得茎和推进疾病治疗的法规。