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Tracing hypoxic state and hypoxia memory in glioblastoma progression

追踪胶质母细胞瘤进展中的缺氧状态和缺氧记忆

基本信息

批准号：
10387061
负责人：
Roland Horst Friedel
金额：
$ 25.36万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-12-15 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10387061
关键词：
Ablation Acute Address Aftercare Cancer Prognosis Cell Hypoxia Cell Line Cells Complement Coupled Data Diffuse Diphtheria Toxin Environment Experimental Designs Exposure to Fluorescence Gene Expression Profile Gene Expression Profiling Genes Genetic Genetic Transcription Glioblastoma Glioma Goals Green Fluorescent Proteins Growth Histologic Hypoxia Hypoxia Inducible Factor Immune response Immunocompetent Infiltration Link Malignant - descriptor Malignant Neoplasms Malignant neoplasm of brain Maps Memory Modeling Molecular Molecular Profiling Molecular Target Mus Necrosis Outcome Oxygen Patients Pattern Physiologic pulse Population Primary Brain Neoplasms Prognosis Radiation therapy Recording of previous events Recurrence Relapse Reporter Reporting Response Elements Role SCID Mice Spatial Distribution Stress and Coping System Tamoxifen Testing Therapeutic Time Tracer Transplant Recipients Transplantation Tumor Tissue alpha Toxin angiogenesis base combat design fitness fluorophore genetic approach innovation insight metabolic fitness migration neoplastic cell prognostic tool programs promoter release factor response single-cell RNA sequencing stem cells stemness therapeutic target transplant model tumor tumor hypoxia tumor progression tumorigenic

项目摘要

Hypoxia is linked to worse prognosis for cancers, including glioblastoma (GBM), the most common and highly lethal primary brain tumor. Hypoxic tumor cells are thought to be better equipped to survive therapy and spawn tumor recurrence, however, the trajectory of hypoxic cells during GBM expansion and their roles in recurrent GBM after therapy remain poorly understood. The main goal of this proposal is to apply a dual genetically encoded hypoxia-sensitive reporter system with lineage tracing capability to systematically characterize hypoxic tumor cells during GBM progression. The dual reporter system distinguishes tumor cells that are acutely hypoxic (marked by green fluorescence) from those with a history of hypoxia exposure (permanently marked with red fluorescence). Their cell fate will be traced across time and space during GBM progression in both primary and recurrent GBM models. The cellular study will be coupled with gene expression analysis on single cell level to unravel the molecular underpinning of malignant potency of hypoxic tumor cells. By comparing transcription profiles of acutely hypoxic versus hypoxia-exposed cells in primary and recurrent GBM, we will test the hypothesis that there exists a hypoxia memory, i.e., hypoxia-exposed cells retaining a set of hypoxia-induced genes that may be linked to survival fitness and tumorigenic potential. In conjunction to the descriptive part of our study, we have also devised a genetic platform to selectively ablate hypoxic population with temporal control to study their contribution to tumor progression in both primary and recurrent GBM. This functional data will provide direct evidence to test the central hypothesis that hypoxia contributes to tumor progression, and more importantly, tumor relapse after treatment. In summary, our innovative study will gain new insights into the link between hypoxia and GBM malignancy, and set the stage for the discovery of new prognostic tools and therapeutics targets to combat GBM.

缺氧与癌症的预后不良有关，包括胶质母细胞瘤（GBM），这是最常见和高度恶性的肿瘤。致命的原发性脑瘤低分化的肿瘤细胞被认为是更好的装备，以生存治疗和产卵然而，肿瘤复发，GBM扩张期间缺氧细胞的轨迹及其在复发中的作用，治疗后的GBM仍然知之甚少。这项建议的主要目标是应用一种双重基因，具有谱系追踪能力的编码缺氧敏感性报告系统 GBM进展过程中的肿瘤细胞。双报告系统区分急性缺氧的肿瘤细胞（用绿色荧光标记）与有缺氧暴露史的人（用红色永久标记）比较荧光）。它们的细胞命运将在原发性和继发性GBM进展期间跨时间和空间追踪。复发性GBM模型。细胞研究将与单细胞水平的基因表达分析相结合，解开缺氧肿瘤细胞恶性潜能的分子基础。通过比较转录在原发性和复发性GBM中急性缺氧与缺氧暴露细胞的概况，我们将测试假设存在缺氧记忆，即，缺氧暴露的细胞保留一组缺氧诱导的可能与生存适应性和肿瘤发生潜力有关的基因。在结合的描述部分，在我们的研究中，我们还设计了一个遗传平台，通过时间控制来选择性地消融缺氧群体。研究它们对原发性和复发性GBM中肿瘤进展的贡献。这些功能数据将提供直接证据来检验缺氧促进肿瘤进展的中心假设，等等。重要是，治疗后肿瘤复发。总之，我们的创新研究将对这一联系有新的认识缺氧和GBM恶性肿瘤之间的关系，并为发现新的预后工具奠定基础，治疗靶点来对抗GBM。