Novel Roles of TAZ and YAP in DNA Damage Repair with 3D Genome Organization and the Therapeutic Resistance in Glioblastoma

项目总结 胶质母细胞瘤(GBM)是一种新生的侵袭性脑癌，对治疗具有抵抗力。一把钥匙 GBM预后不良的原因是一种称为胶质瘤干细胞(GSCs)的细胞亚群 传统的细胞毒疗法，并作为复发的肿瘤重新填充。对分子的更全面的理解 GSCs的生物学和治疗耐药的潜在机制是必需的。我们的小组已经证明了TAZ， 转录辅助因子在大约70%的基底膜中高度表达。Taz和它的Paralog Yap是致癌的 脑瘤进展的驱动力。高表达TAZ的GSC经历原神经向间充质亚型转变 过渡。TAZ驱动的细胞命运改变伴随着侵袭性行为，如分级增加、坏死 和抗辐射能力。沉默YAP/TAZ通过激活神经原程序来消除肿瘤生长，从而使 这些蛋白质具有诱人的治疗靶点。虽然YAP/TAZ的致癌功能已经确立 在GBM中，细胞命运转变的确切分子机制及其对治疗的贡献 抗药性还没有完全被理解。我们现在已经积累了大量的证据来确定 YAP/TAZ在DNA损伤反应通路中，是一个感知和修复DNA损伤的蛋白质网络 对电离辐射(IR)治疗的反应。YAP/TAZ也是由增强子重新编程和招募引起的 原神经和间充质基因增强子中不同的分子复合体，提供对DNA的保护 破坏基因组的脆弱区域。在这个方案中，我们将深入研究分子机制。 潜在的YAP/TAZ驱动的神经源性程序控制和放射抗性 最先进的分子、细胞和生化方法。重要的是，我们将评估治疗 使用临床前模型研究YAP/TAZ的新型药物抑制剂联合IR的益处 GBM。这些研究的成功完成不仅将揭开背后的机械基础 GBM的神经元分化和DNA损伤修复，也为下一代神经干细胞的发展提供了信息 GBM的临床试验。

PROJECT SUMMARY Glioblastoma (GBM) is an aggressive type of brain cancer that arises de novo and is therapy resistant. A key contributor to poor outcomes in GBM is a subpopulation of cells called glioma stem-like cells (GSCs) that evade conventional cytotoxic therapies and repopulate as recurrent tumors. A fuller understanding of the molecular mechanisms underlying the biology and therapy resistance of GSCs is required. Our group has shown that TAZ, a transcriptional co-factor is highly expressed in about 70% of GBMs. TAZ and its paralog YAP are oncogenic drivers of brain tumor progression. GSCs overexpressing TAZ undergo a proneural to mesenchymal subtype transition. TAZ driven cell fate change is accompanied by aggressive behavior such as increased grade, necrosis and radio-resistance. Silencing YAP/TAZ ablates tumor growth by activating neurogenic programs, thus making these proteins attractive therapeutic targets. Although the oncogenic functions of YAP/TAZ are well established in GBM, the exact molecular mechanisms underlying cell fate transition and their contribution to therapy resistance are not fully understood. We have now accumulated substantial evidence to pinpoint a direct role for YAP/TAZ in DNA damage response pathway, a network of proteins that sense and repair DNA lesions in response to ionizing radiation (IR) treatments. YAP/TAZ also cause by enhancer reprogramming and recruitment of distinct molecular complexes in proneural and mesenchymal gene enhancers, which offers protection of DNA damage vulnerable regions of the genome. In this proposal, we will deeply investigate the molecular mechanisms underlying YAP/TAZ driven control of neurogenic programs and radio-resistance using both conventional and state-of-the-art molecular, cellular and biochemical approaches. Importantly, we will evaluate the therapeutic benefit of novel pharmacological inhibitors of the YAP/TAZ in combination with IR using pre-clinical models of GBM. Successful completion of these studies will not only unravel the mechanistic underpinnings behind neuronal differentiation and DNA damage repair in GBM, but also inform the development of next generation of clinical trials for GBM.