Polycomb and Cellular Hierarchy in the Brain

描述（由申请人提供）：胶质瘤在肿瘤内显示出分化状态的层次结构，类似于正常脑发育，其中干细胞在自我更新和分化状态之间保持动态平衡。事实上，启动和维持胶质瘤的分子信号通常与正常大脑发育中涉及的分子信号重叠。干细胞程序可能是癌症促进其恶性程度的关键要求，这一直是癌症干细胞（CSC）模型的基本概念。一些癌症可能不遵循CSC模型，并且CSC仍然存在争议;然而，来自多个实验室的严格功能研究已经鉴定并表征了胶质瘤中的CSC。多形性胶质母细胞瘤（GBM）是最常见和最致命的胶质瘤形式，目前的治疗仅提供姑息治疗。由于GBM干细胞（GSC）对常规治疗具有抗性，因此了解GSC维持的机制并设计新的靶向策略非常重要。我们对Polycomb通路感兴趣，因为它是负责胚胎发育、神经干细胞命运决定和GBM恶性肿瘤的关键表观遗传调节因子。Zeste同源物增强子2（EZH 2）是一种Polycomb复合物的组蛋白赖氨酸甲基转移酶，可介导正常和肿瘤性脑干细胞中促分化基因的转录抑制。我们先前表明EZH 2优先在GSC中表达，并且EZH 2介导的转录沉默促进GSC。在初步研究中，我们已经确定EZH 2蛋白直接结合并激活信号转导和转录激活因子3（STAT 3），这表明Polycomb途径具有新的作用。该提案的中心目标是研究EZH 2不仅介导转录沉默，而且还有助于GBM中STAT 3信号转导的激活的假设，并将这些知识转化为新治疗方法的开发。为了验证这一假设，我们将首先通过一系列生物化学和遗传学方法来研究EZH 2激活STAT 3的分子机制。其次，我们将评估EZH 2在人GBM异种移植物和小鼠胶质瘤中的这种新提出的功能的体内生物学效应。最后，我们将进行临床前研究，以评估靶向EZH 2-STAT 3相互作用的治疗效果，并确定预测最大治疗反应的生物标志物。我们预计，这些拟议研究的完成将为Polycomb生物学提供一种新的范式，并为靶向STAT 3提供一种新的治疗方法，这可能会导致转化为改进的疗法。

DESCRIPTION (provided by applicant): Gliomas display a hierarchy of differentiation states within the tumor, similar to normal brain development in which stem cells maintain a dynamic balance between the state of self-renewal and differentiation. Indeed, molecular signals that initiate and maintain gliomas commonly overlap with those involved in normal brain development. Stem cell programs can be a critical requirement for cancers to promote their malignancy, which has been an underlying concept of the cancer stem cell (CSC) model. Some cancers may not follow the CSC model and CSCs remain controversial; however, rigorous functional studies from multiple laboratories have identified and characterized CSCs in gliomas. Glioblastoma multiforme (GBM) is the most common and most lethal form of gliomas with current therapy providing only palliation. As GBM stem cells (GSCs) are resistant to conventional therapy, it is important to understand mechanisms involved in GSC maintenance and devise new strategies to target them. We are interested in the Polycomb pathway, as it is a critical epigenetic regulator responsible for embryonic development, fate decision of neural stem cells, and GBM malignancy. Enhancer of Zeste Homolog 2 (EZH2), a histone lysine methyl transferase of Polycomb complex, mediates transcriptional repression of pro-differentiation genes in both normal and neoplastic brain stem cells. We previously showed that EZH2 is preferentially expressed in GSCs and that EZH2-mediated transcriptional silencing promotes GSCs. In preliminary studies, we have identified that the EZH2 protein directly binds to and activates Signal Transducer and Activator of Transcription 3 (STAT3), suggesting a novel role for the Polycomb pathway. The central goals of this proposal are to investigate the hypothesis that EZH2 not only mediates transcriptional silencing but also contributes to the activation of STAT3 signaling in GBM, and to translate this knowledge to the development of new therapeutic approaches. To test this hypothesis, we will first interrogate the molecular mechanisms through which EZH2 activates STAT3, by utilizing a series of biochemical and genetic approaches.)Second, we will evaluate in vivo biological effects of this newly proposed function of EZH2 in human GBM xenografts and mouse gliomas. Finally, we will perform preclinical studies to evaluate the therapeutic efficacy of targeting the EZH2-STAT3 interaction, and identify biomarkers that predict maximal therapeutic responses.)We anticipate that completion of these proposed studies will yield a new paradigm for Polycomb biology and a novel therapeutic approach to target STAT3, which may lead to the translation into improved therapies.