Polycomb and Cellular Hierarchy in the Brain

描述(申请人提供)：胶质瘤在肿瘤内表现出一系列分化状态，类似于正常的脑发育，干细胞在自我更新和分化状态之间保持动态平衡。事实上，引发和维持胶质瘤的分子信号通常与参与正常大脑发育的分子信号重叠。干细胞计划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，CSCs仍然存在争议；然而，来自多个实验室的严格的功能研究已经识别和表征了胶质瘤中的CSCs。多形性胶质母细胞瘤(GBM)是最常见和最致命的胶质瘤，目前的治疗只能提供姑息治疗。由于GBM干细胞(GSCs)对常规治疗具有抵抗力，了解GSC维持的机制并设计新的靶向策略是很重要的。我们对Polycomb通路很感兴趣，因为它是一个关键的表观遗传调节因子，负责胚胎发育、神经干细胞的命运决定和GBM恶性肿瘤。Zust Homolog 2增强子(EZH2)是一种多梳复合体的组蛋白赖氨酸甲基转移酶，在正常和肿瘤脑干细胞中介导促分化基因的转录抑制。我们之前的研究表明，EZH2在GSCs中优先表达，EZH2介导的转录沉默促进GSCs的表达。在初步研究中，我们已经确定EZH2蛋白直接与信号转导和转录激活因子3(STAT3)结合并激活，这表明Polycomb途径具有新的作用。该建议的中心目标是研究EZH2不仅介导转录沉默而且有助于激活GBM中的STAT3信号的假设，并将这一知识转化为新的治疗方法的开发。为了验证这一假设，我们首先将利用一系列生化和遗传学方法来询问EZH2激活STAT3的分子机制。)其次，我们将在体内评估EZH2这一新提出的功能在人GBM移植瘤和小鼠胶质瘤中的生物学效应。最后，我们将进行临床前研究，以评估靶向EZH2-STAT3相互作用的治疗效果，并确定预测最大治疗反应的生物标记物。)我们预计，这些拟议研究的完成将产生Polycomb生物学的新范式和靶向STAT3的新治疗方法，这可能导致转化为改进的治疗方法。

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.