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Dissecting the role of ATRX in soft tissue sarcoma development and radiation response

剖析 ATRX 在软组织肉瘤发展和放射反应中的作用

基本信息

批准号：
10348692
负责人：
Robert Warren Floyd
金额：
$ 2.97万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-01 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10348692
关键词：
ATRX gene Affect Biological Assay Biological Models Cancer Burden Cancer Patient Caring Cell Line Centromere Clinical Connective Tissue Cre-LoxP DNA Damage DNA Repair DNA Sequence Alteration Data Defect Development Double Strand Break Repair Fluorescent in Situ Hybridization Frameshift Mutation Functional disorder Genes Genetic Determinism Genetically Engineered Mouse Genomic Instability Glioma Goals Growth Histones Human Immune signaling Immunofluorescence Immunologic Immunotherapy Impairment In Situ Hybridization In Vitro Innate Immune Response Ionizing radiation KRAS oncogenesis KRASG12D Knock-out Knowledge Lead Link Maintenance Malignant Neoplasms Measurement Mental Retardation Mission Mitotic Modeling Molecular Chaperones Mouse Cell Line Mus Mutate Mutation Natural Immunity Nonhomologous DNA End Joining Oncogenes Pathway interactions Patients Prediction of Response to Therapy Prevalence Prognosis Proteins Public Health Radiation Radiation Tolerance Radiation therapy Radiosensitization Repetitive Sequence Research Research Personnel Role Sampling Signal Transduction Soft tissue sarcoma Stains Stimulator of Interferon Genes Survival Rate System Technology Telomerase Testing The Cancer Genome Atlas Therapeutic Intervention Tumor Cell Line Western Blotting alpha-Thalassemia base cancer type cell growth cell type conditional mutant glioma cell line homologous recombination immunogenicity improved in vivo in vivo Model innate immune pathways insight knock-down loss of function mutation mouse model next generation sequencing novel novel therapeutics prognostic of survival radiation response recombinase response sarcoma segregation telomere treatment response tumor tumor behavior tumor growth

项目摘要

ABSTRACT: Soft tissue sarcomas are tumors of the connective tissue that account for an estimated 12,000 new cancer cases annually and carry a poor prognosis with a five year survival rate of 50% despite treatment. An important research objective in improving therapy for soft tissue sarcoma patients is to understand how genetic mutations affect soft tissue sarcoma development and radiation response. Intriguingly, next- generation sequencing data from The Cancer Genome Atlas and other massive cancer sequencing efforts have identified Alpha Thalassemia and Mental Retardation X-linked, or ATRX, as the second most frequently mutated gene in soft tissue sarcoma. ATRX is perhaps best known for its role as regulator of alternative lengthening of telomeres (ALT), a telomerase independent tumor maintenance mechanisms found in 15% of all human cancers. Interestingly, ATRX is predictive for overall survival in multiple human cancers and researchers recently demonstrated that ATRX knockdown leads to radiosensitization in glioma cell lines. Despite the clear importance of this gene in multiple human cancers and its frequent alteration in soft tissue sarcoma, the role of ATRX in soft tissue sarcoma remains relatively unstudied. The long term goal of this project is to improve the efficacy of current therapies for soft tissue sarcoma patients and enable the development of novel therapeutics for the treatment of human cancers. The overall goal of this proposal is to determine the effect of Atrx deletion on the radiosensitivity and innate immune response of soft tissue sarcoma. To achieve this, the Cre-LoxP recombinase system has been used in genetically engineered mouse models to generate the first primary mouse model of soft tissue sarcoma with ATRX deletion. The central hypothesis is that loss of ATRX impairs DNA damage repair, delays tumor development and increases radiosensitivity in soft tissue sarcoma. To test this hypothesis, primary soft tissue sarcomas with ATRX deletion will be compared to primary soft tissue sarcomas that retain Atrx. Using in vitro and in vivo model systems generated using Cre-LoxP and dual recombinase technologies, I will test this hypothesis in three specific aims: Aim 1: Investigate the effect of Atrx deletion on tumor growth and repetitive element associated mitotic dysfunction in a primary mouse model of soft tissue sarcoma Aim 2: Determine the role of ATRX in DNA damage repair and sarcoma response to ionizing radiation Aim 3: Determine the effect of Atrx deletion on radiation induced mitotic dysfunction and cGAS-STING innate immune signaling in sarcoma

抽象的：软组织肉瘤是结缔组织肿瘤，估计有 12,000 例新发肿瘤每年都会有癌症病例，预后很差，尽管接受治疗，五年生存率为 50%。改善软组织肉瘤患者治疗的一个重要研究目标是了解基因突变如何影响软组织肉瘤的发展和放射反应。有趣的是，接下来—— 来自癌症基因组图谱和其他大规模癌症测序的一代测序数据努力已确定阿尔法地中海贫血和 X 连锁智力迟钝 (ATRX) 是第二大软组织肉瘤中经常突变的基因。 ATRX 最出名的或许是它作为监管者的角色端粒选择性延长（ALT），一种独立于端粒酶的肿瘤维持机制 15% 的人类癌症中都发现了这种物质。有趣的是，ATRX 可预测多种疾病的总体生存率人类癌症和研究人员最近证明 ATRX 敲低会导致放射增敏在神经胶质瘤细胞系中。尽管该基因在多种人类癌症中具有明显的重要性并且其频繁出现尽管 ATRX 在软组织肉瘤中的改变，但 ATRX 在软组织肉瘤中的作用仍然相对未经研究。该项目的长期目标是提高当前软组织肉瘤疗法的疗效患者并能够开发治疗人类癌症的新疗法。整体该提案的目标是确定 Atrx 缺失对放射敏感性和先天免疫的影响软组织肉瘤的反应。为了实现这一目标，Cre-LoxP 重组酶系统已被用于基因工程小鼠模型产生了第一个原代软组织肉瘤小鼠模型 ATRX 删除。核心假设是 ATRX 的缺失会损害 DNA 损伤修复，延迟肿瘤发生发展并增加软组织肉瘤的放射敏感性。为了检验这个假设，初级软将具有 ATRX 缺失的组织肉瘤与保留 Atrx 的原发性软组织肉瘤进行比较。使用使用 Cre-LoxP 和双重组酶技术生成的体外和体内模型系统，我将在三个具体目标上检验这一假设：目标1：研究Atrx缺失对肿瘤生长和相关重复元件的影响原代小鼠软组织肉瘤模型的有丝分裂功能障碍目标 2：确定 ATRX 在 DNA 损伤修复和肉瘤对电离辐射反应中的作用目标 3：确定 Atrx 缺失对辐射诱导的有丝分裂功能障碍和 cGAS-STING 的影响肉瘤中的先天免疫信号传导