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.

项目概要 胶质母细胞瘤 (GBM) 是一种侵袭性脑癌，从头产生且对治疗有抵抗力。一把钥匙 导致 GBM 预后不良的一个因素是一种称为神经胶质瘤干细胞样细胞 (GSC) 的细胞亚群，它们会逃避 传统的细胞毒性疗法并重新增殖为复发性肿瘤。对分子的更全面的了解 需要了解 GSC 的生物学和治疗耐药性的潜在机制。我们的小组已经证明 TAZ， 转录辅助因子在约 70% 的 GBM 中高度表达。 TAZ 及其旁系同源物 YAP 具有致癌性 脑肿瘤进展的驱动因素。过度表达 TAZ 的 GSC 经历原神经亚型到间充质亚型 过渡。 TAZ驱动的细胞命运改变伴随着攻击行为，例如等级增加、坏死 和抗辐射性。沉默 YAP/TAZ 通过激活神经源性程序来消除肿瘤生长，从而使 这些蛋白质具有吸引力的治疗靶点。尽管 YAP/TAZ 的致癌功能已得到充分证实 在 GBM 中，细胞命运转变的确切分子机制及其对治疗的贡献 阻力尚未完全了解。我们现在已经积累了大量证据来确定 DNA 损伤反应通路中的 YAP/TAZ，这是一个感知和修复 DNA 损伤的蛋白质网络 对电离辐射（IR）治疗的反应。 YAP/TAZ 也是由增强子重编程和招募引起的 原神经和间充质基因增强子中的不同分子复合物，可提供 DNA 保护 损害基因组的脆弱区域。在本提案中，我们将深入研究分子机制 潜在的 YAP/TAZ 驱动控制神经源性程序和放射抗性，使用传统和 最先进的分子、细胞和生化方法。重要的是，我们将评估治疗效果 使用 YAP/TAZ 的新型药物抑制剂与 IR 联合使用的临床前模型的益处 GBM。这些研究的成功完成不仅将揭示其背后的机制基础 GBM 中的神经元分化和 DNA 损伤修复，也为下一代的发展提供信息 GBM 的临床试验。