Epigenetic regulation of LDOC1 drives tumor biology in high risk ependymoma

项目总结 脑瘤已成为儿童癌症相关死亡的主要原因。室管膜瘤(EPN) 在这些死亡中占了相当大的比例。超过70%的患有室管膜瘤的儿童 复发，几乎所有复发的儿童最终都会死亡。与髓母细胞瘤不同，没有有效的 室管膜瘤的化疗已经被开发出来，以补充标准，并最终用于大多数 无效，手术和放射治疗。尤其是患有最常见类型的室管膜瘤的儿童， 后颅窝A组(PFA1)，复发更频繁，经历更多侵袭性、转移性疾病 旧病复发。因此，迫切需要更有效的治疗方法来对抗高危PFA1肿瘤。单细胞 RNA测序数据表明，在特定的肿瘤亚群中，LDOC1的表观遗传学沉默 细胞对PFA1肿瘤的肿瘤生物学有深远的、直接的影响。驱动假说是 由于染色质重塑，MEC亚群中LDOC1的表观遗传沉默是 PFA1EPN中的分子驱动因素，通过上调非典型性NF-B的激活。要解决这个问题 假设，目标一中的研究将通过检查1)来确定LDOC1表达在EPN中的作用 基因沉默的机制，2)体内和体外LDOC1缺失的功能作用，3)基因组 LDOC1的转录靶点。目标二旨在1)确定LDOC1如何监管非规范 2)确定NF-B信号通路的功能后果。集体 拟议的研究将定义LDOC1丢失的影响，我们假设这是分子驱动因素 PFA1 EPN的肿瘤生物学研究这些研究将大大增加我们对儿童EPN和 有可能为患有这种高危、预后不良的儿童确定合理的治疗目标 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.