Identification and targeting of mechanisms specific to glioma stem cells in glioblastoma

胶质母细胞瘤中胶质瘤干细胞特异性机制的鉴定和靶向

• 批准号: 9756347
• 负责人: DANIEL J BRAT
• 金额: $ 35.79万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9756347
• 关键词: Automobile Driving; Behavior; Biological; Biology; Brain Neoplasms; Brain Stem Neoplasms; CDK5 gene; CXCR4 gene; Cell division; Cell physiology; Cells; Data; Daughter; Development; Drosophila genus; Dyes; Equilibrium; Gene Targeting; Genes; Genetic; Genetically Engineered Mouse; Glioblastoma; Glioma; Goals; Growth; Human; Hypoxia; In Vitro; Lasers; Lead; Malignant - descriptor; Malignant Glioma; Malignant neoplasm of brain; Microscopic; Molecular; Mus; Mutate; Necrosis; Necrosis Induction; Neoplasms; Nervous system structure; Orthologous Gene; Pathway interactions; Pattern; Pharmacology; Phenotype; Primary Brain Neoplasms; Process; Property; Proteins; Recurrence; Rose Bengal; Self-Direction; Signal Transduction; Stem cells; Study models; System; Techniques; Therapeutic; Thrombosis; Time; Tumor Stem Cells; Tumor Suppressor Proteins; Tumorigenicity; Up-Regulation; Work; Xenograft Model; Xenograft procedure; cranium; daughter cell; human model; in vivo; in vivo Model; inhibitor/antagonist; migration; mouse model; multiphoton microscopy; neoplastic; neoplastic cell; nestin protein; neuroblast; novel; novel therapeutics; outcome forecast; photoactivation; pluripotency; pre-clinical; programs; response; self-renewal; stem; stemness; targeted treatment; therapeutic target; therapy resistant; treatment strategy; tumor growth; tumor microenvironment

Project Summary/Abstract Glioblastoma (GBM) is the most common and most malignant primary brain tumor and has a dismal prognosis. Abundant evidence now indicates that a small subset of neoplastic cells, referred to as Glioma Stem Cells (GSCs), governs biologic behavior and resistance to therapy. GSCs inhabit specific biologic niches and have properties of self-renewal, pluripotency and high tumorigenicity. They can be identified by expression of markers, such as CD133, CD15 and nestin, yet molecular mechanisms responsible for their specific stem-like behavior in glioblastomas have not been fully defined. This proposal aims to define mechanisms underlying fundamental biological properties of GSCs, including: 1) their marked accumulation following the development of necrosis and tendency to localize to the hypoxic niche; and 2) a disrupted program of asymmetric cell division that favors self-renewing division over differentiation. We have developed novel in vitro and in vivo models and analytic techniques to study the differential behavior of stem and non-stem glioma cells within the tumor micro-environment, especially as it relates to their accumulation in regions of hypoxia. These include an in vivo orthotopic xenograft model in which stem cells are interrogated for patterns and mechanisms of accumulation following the induction of necrosis using a photo-activated dye. We also dissect pathways that direct asymmetric cellular division in Drosophila nervous system provide clues to understand the stem/non-stem dynamics in malignant gliomas. We have previously demonstrated that the human ortholog of Drosophila Brat, Trim3, is a tumor suppressor that regulates glioma stem cell dynamics and promotes stemness when lost. Here we propose to investigate novel regulatory mechanisms that arise during transition to the stem cell phenotype that can be antagonized therapeutically. Regulatory networks and potential therapeutic targets are further explored in xenografts and genetically engineered mouse models that recapitulates human gliomas to show efficacy.

项目摘要/摘要 胶质母细胞瘤(GBM)是最常见和最恶性的原发脑肿瘤， 预后不佳。大量证据现在表明，一小部分 肿瘤细胞，被称为胶质瘤干细胞(GSCs)，控制着生物行为 以及对治疗的抗拒。GSC生活在特定的生物生态位中，并具有以下特性 自我更新、多能性和高致瘤性。他们可以通过表情来识别 CD133、CD15和Nestin等标记的分子机制 对于它们在胶质母细胞瘤中特定的干细胞样行为还没有完全定义。这 该提案旨在定义潜在的基本生物学特性的机制 GSCs，包括：1)随着坏死的发展而显著堆积 和倾向于局限于低氧生态位；以及2)不对称的中断程序 有利于自我更新的分裂而不是分化的细胞分裂。我们已经开发出 研究差异的新的体内外模型和分析技术 干细胞和非干细胞胶质瘤细胞在肿瘤微环境中的行为， 尤其是当它与它们在缺氧区的积累有关时。其中包括一个In 体内原位异种移植模型，在该模型中，干细胞被询问模式和 用光激活的方法诱导坏死后的堆积机制 染料。我们还剖析了指导果蝇细胞不对称分裂的途径 神经系统为了解恶性肿瘤的干/非干动力学提供线索 神经胶质瘤。我们之前已经证明了果蝇幼虫的人类直系同源基因， Trim3，是一种肿瘤抑制因子，调节胶质瘤干细胞动力学并促进 迷失时的干枯。在这里，我们建议研究新的监管机制， 在向干细胞表型的转变过程中出现，可被拮抗 从治疗上讲。监管网络和潜在的治疗靶点进一步 在异种移植和基因工程小鼠模型中探索 人类神经胶质瘤显示出疗效。