Epigenetic regulation of LDOC1 drives tumor biology in high risk ependymoma

项目摘要 脑肿瘤已成为儿童癌症相关死亡的主要原因。室管膜瘤（EPN） 造成了大量的死亡超过70%的室管膜瘤患儿 几乎所有复发的儿童最终都会死亡。与髓母细胞瘤不同， 化疗已经发展到室管膜瘤，以补充标准，并最终为大多数 无效的手术和放疗尤其是患有最常见的室管膜瘤的儿童， 后颅窝A组（PFA 1），复发更频繁，在 复发因此，迫切需要更有效的治疗方法来对抗高风险的PFA 1肿瘤。单细胞 RNA测序数据表明，LDOC 1在特定肿瘤亚群中的表观遗传沉默， 细胞对PFA 1肿瘤的肿瘤生物学具有深远的直接影响。驱动假设是， MEC亚群中LDOC 1的表观遗传沉默，作为染色质重塑的结果，是 PFA 1 EPN中的分子驱动因子，通过上调非经典NF-κ B B活化。为了解决这个 假设，目的一的研究将通过检查1）EPN中LDOC 1表达的作用， 基因沉默的机制，2）LDOC 1在体外和体内丢失的功能作用，以及3）基因组沉默的机制。 LDOC 1的转录靶点。目的二：1）确定LDOC 1如何调节非经典的 NF-κ B B信号传导和2）鉴定NF-κ B B信号传导途径的功能后果。集体 拟议的研究将确定LDOC 1损失的影响，我们假设这是分子驱动因素， PFA 1 EPN的肿瘤生物学。这些研究将大大增加我们对儿童EPN的理解， 有可能为这种高风险、预后差的儿科疾病的儿童确定合理的治疗靶点。 脑瘤

PROJECT SUMMARY Brain tumors have become the leading cause of cancer-related death in children. Ependymoma (EPN) accounts for a substantial number of these deaths. Over 70% of children presenting with ependymoma will relapse and almost all children who relapse will eventually die. Unlike medulloblastoma, no effective chemotherapy has been developed in ependymoma to complement the standard, and eventually for most ineffectual, surgery and radiation. In particular, children with the most common type of ependymoma, posterior fossa Group A (PFA1), relapse more frequently and experience more invasive, metastatic disease at relapse. Thus, there is a critical need for more effective therapies to combat high-risk PFA1 tumors. Single-cell RNAsequencing data suggest that the epigenetic silencing of LDOC1 within a specific subpopulation of tumor cells has a profound, direct impact on the tumor biology of PFA1 tumors. The driving hypothesis is that epigenetic silencing of LDOC1 with in the MEC subpopulation, as a result of chromatin remodeling, is the molecular driver in PFA1 EPN, through upregulation of non-canoncial NF-B activation. To address this hypothesis, the studies in aim one will determine the role of LDOC1 expression in EPN by examining 1) the mechanism of gene silencing, 2) the functional role of loss of LDOC1 in vitro and in vivo, and 3) the genomic transcriptional targets of LDOC1. Aim two is designed to 1) determine how LDOC1 regulates non-canoncial NF-B signaling and 2) identify the functional consequences of the NF-B signaling pathway. The collective proposed studies will define the effect of LDOC1 loss, which we hypothesize to be the molecular driver of tumor biology of PFA1 EPN. These studies will significantly add to our understanding of childhood EPN and have the potential to identify rational therapeutic targets for children with this high-risk, poor-outcome pediatric brain tumor.