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

TAZ 和 YAP 在 3D 基因组组织 DNA 损伤修复中的新作用以及胶质母细胞瘤的治疗耐药性

• 批准号: 10649830
• 负责人: KRISHNA PL BHAT
• 金额: $ 45.55万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10649830
• 关键词: 3-Dimensional; Adult; Affect; Aggressive behavior; American; Architecture; Binding; Biochemical; Biological; Biological Assay; Biology; Brain Neoplasms; Catalytic Domain; Cells; ChIP-seq; Chromatin; Chromatin Structure; Clinical Trials; Clustered Regularly Interspaced Short Palindromic Repeats; Complex; Cytotoxic Chemotherapy; DNA; DNA Damage; DNA Double Strand Break; DNA Repair; DNA lesion; DNA-dependent protein kinase; Data; Development; Disease; Double Strand Break Repair; Enhancers; Genes; Genetic Transcription; Genome; Glioblastoma; Glioma; Growth; Heterochromatin; Hi-C; In Vitro; Ionizing radiation; Kinetics; Knowledge; Malignant neoplasm of brain; Mediating; Mesenchymal; Molecular; Molecular Biology; Mus; Necrosis; Neighborhoods; Neuronal Differentiation; Neurons; Nonhomologous DNA End Joining; Nuclear Translocation; Oncogenic; Outcome; Pathway interactions; Patients; Phosphorylation; Play; Pre-Clinical Model; Proteins; Radiation therapy; Radiosensitization; Recurrent tumor; Reducing Agents; Reporter; Resistance; Role; Scaffolding Protein; Serine; Site; Structure; Survival Analysis; Technology; Testing; Therapeutic; Threonine; Transcription Factor AP-1; Verteporfin; XRCC5 gene; Xenograft procedure; cancer clinical trial; cancer type; clinically relevant; cofactor; cohesin; cohesion; confocal imaging; epigenomics; immune checkpoint blockade; improved; in vitro Assay; in vivo; inhibitor; irradiation; mouse model; next generation; novel; novel therapeutics; overexpression; paralogous gene; pharmacologic; programs; protein complex; radiation resistance; recruit; response; stem; stem-like cell; targeted treatment; therapeutic target; therapy resistant; transcription factor; transdifferentiation; tumor ablation; tumor growth; tumor progression

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.

项目摘要 胶质母细胞瘤（GBM）是一种侵略性的脑癌，它是从头出现的，具有耐药性。钥匙 GBM中不良预后的贡献者是逃避胶质瘤干细胞（GSC）细胞的亚群 常规的细胞毒性疗法并作为复发性肿瘤重新填充。对分子的更深刻理解 需要GSC的生物学和治疗性抗性的机制。我们的小组表明TAZ， 转录共同因素在约70％的GBM中高度表达。 TAZ及其旁系同源物是致癌的 脑肿瘤进展的驱动因素。过表达TAZ的GSC经历了胸膜和间充质亚型 过渡。 TAZ驱动的细胞命运变化伴随着侵略性行为，例如增加等级，坏死 和抗性。通过激活神经源性程序，使YAP/TAZ逐渐消除肿瘤的生长，从而使 这些蛋白质有吸引力的治疗靶标。虽然YAP/TAZ的致癌功能已建立 在GBM中，细胞命运转变的确切分子机制及其对治疗的贡献 抗性尚未完全理解。现在，我们积累了大量证据，以查明直接作用 DNA损伤响应途径中的YAP/TAZ，这是一种感知和修复DNA病变的蛋白质网络 对电离辐射（IR）处理的反应。 yap/taz也通过增强器重新编程和招聘引起 龙骨和间充质基因增强子中不同分子复合物的不同，可提供DNA的保护 损害基因组的脆弱区域。在此提案中，我们将深入研究分子机制 YAP/TAZ的基础驱动了对神经源性程序的控制和抗性的控制 最先进的分子，细胞和生化方法。重要的是，我们将评估治疗性 YAP/TAZ的新型药理抑制剂与IR结合使用IR的好处 GBM。这些研究的成功完成不仅会揭示背后的机械基础 GBM中的神经元分化和DNA损伤修复，但也告知下一代 GBM的临床试验。