Modeling the Glioblastoma Microenvironment to Uncover Progression Mechanisms and Therapeutic Targets

模拟胶质母细胞瘤微环境以揭示进展机制和治疗靶点

• 批准号: 10611990
• 负责人: DANIEL J BRAT
• 金额: $ 49.52万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10611990
• 关键词: 3-Dimensional; Acceleration; Animal Model; Animals; Automobile Driving; Biological; Brain; Brain Neoplasms; CD34 gene; CXCR4 gene; Cells; Cessation of life; Coagulation Process; Complex; Data; Development; Disease Outcome; Disease Progression; Elements; Etiology; Event; Evolution; Genetic; Genetic Transcription; Glioblastoma; Glioma; Growth; Human; Hypoxia; Immune; Immune system; Immunocompetent; In Vitro; Infiltration; Investigation; Label; Lasers; Link; Literature; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of brain; Mesenchymal; Methods; Microscope; Microscopic; Modeling; Molecular; Mus; Mutation; NF1 mutation; Necrosis; Necrosis Induction; PDGFB gene; Patients; Pattern; Phase; Primary Brain Neoplasms; Process; Proliferating; Property; Radial; Radial Growth Phase; Recurrence; Role; Rose Bengal; Sampling; Shapes; Signal Transduction; TP53 gene; Textbooks; Therapeutic; Therapeutic Intervention; Thrombosis; Time; Tumor Cell Migration; Tumor Expansion; Tumor-associated macrophages; Up-Regulation; Vascular blood supply; Visualization; Xenograft procedure; angiogenesis; antagonist; cell motility; cell type; clinically relevant; cranium; human disease; improved; improved outcome; in vivo; innovation; microsystems; migration; monocyte; mouse model; multiphoton microscopy; novel; novel therapeutics; patient derived xenograft model; photoactivation; radiation resistance; recruit; segregation; spatiotemporal; stem cells; stemness; targeted treatment; therapeutic target; therapeutically effective; therapy development; therapy resistant; time use; translational applications; tumor; tumor growth; tumor microenvironment; tumorigenic

In nearly all forms of human cancer, the development of necrosis is tightly linked with malignant progression. Whether necrosis accelerates progression or is largely passive remains an open question, yet modeling these events to establish mechanisms and therapeutic vulnerabilities in animals has been challenging. In glioblastoma (GBM; WHO grade IV), the most malignant primary brain tumor, the rapid, radial growth phase that leads quickly to death is consistently preceded by the development of central necrosis. While genetic alterations of GBM are known in great detail, the biological properties that result from their acquisition and lead to this accelerated growth phase require deeper investigation. The tumor microenvironment (TME) changes dramatically following the onset of necrosis, from a sheet-like growth of infiltrating cells with relatively constant growth properties to a highly complex and evolving 3-D microsystem composed of diverse cell types and spatially segregated signaling networks. To better understand the dynamic temporal and spatial changes that promote progression, we propose to advance mouse models that closely parallel these events in human gliomas, since many mouse models of GBM lack necrosis. We developed a novel method to induce focal necrosis within high grade gliomas in vivo and will study TME restructuring and its impact on glioma growth in real time using multiphoton microscopy. As translational applications, we will demonstrate how hypoxia and necrosis promote the enrichment of glioma stem cells (GSCs) in their peri-necrotic niche and lead to the dramatic influx of tumor-associated macrophages (TAMs), which increase in number over 10-fold in the human disease. We propose both genetically characterized patient-derived GBM xenografts grown in mice with humanized immune cells, as well as an immunocompetent RCAS/tv-a model, and will determine how antagonizing these processes impact disease progression and outcomes. Our preliminary data and the literature indicate substantial differences between pre-necrotic and necrotic gliomas with regard to GSC and TAM enrichment and their impact on biological properties, but the mechanisms and evolution have not been studied in depth, in large part due to the absence of a credible animal model. Our model will capture glioma growth dynamics, GSC enrichment, and TAM influx, and facilitate the development of therapies that antagonize these mechanisms to improve outcomes.

在几乎所有形式的人类癌症中，坏死的发展与 恶性进展。坏死是加速进展还是在很大程度上是被动的 仍然是一个悬而未决的问题，但对这些事件进行建模以建立机制和 动物的治疗脆弱性一直是具有挑战性的。在胶质母细胞瘤(GBM；WHO IV级)，恶性程度最高的原发脑肿瘤，呈放射状快速生长期 迅速导致死亡总是发生在中心性坏死之前。 虽然基底膜的遗传改变是非常详细的已知，但 并导致这一加速增长阶段需要更深层次的 调查。术后肿瘤微环境(TME)发生显著变化 起病坏死，由片状生长的浸润性细胞相对恒定 由以下组成的高度复杂和不断演变的三维微系统的生长特性 多样化的小区类型和空间隔离的信令网络。为了更好地理解 促进进步的动态时间和空间变化，我们建议 先进的小鼠模型，在人类胶质瘤中与这些事件非常相似，因为许多 小鼠肾小球基底膜缺乏坏死。我们开发了一种新的方法来诱导焦点 体内高级别胶质瘤内的坏死，并将研究TME重组及其 用多光子显微镜实时观察对胶质瘤生长的影响。作为翻译 应用，我们将演示缺氧和坏死如何促进血管内皮细胞的浓缩 胶质瘤干细胞(GSCs)在其坏死区周围，并导致戏剧性的涌入 肿瘤相关巨噬细胞(TAM)，其数量增加了10倍以上 人类疾病。我们提出了两种具有遗传特征的患者来源的GBM 在带有人源化免疫细胞的小鼠体内生长的异种移植，以及 免疫活性RCAS/TV-A模型，并将确定如何拮抗这些 过程影响疾病的进展和结果。我们的初步数据和 文献表明，在坏死性胶质瘤和坏死性胶质瘤之间存在显著差异。 关于GSC和的富集物及其对生物学特性的影响，但 机制和进化还没有被深入研究，这在很大程度上是由于 缺乏可信的动物模型。我们的模型将捕捉到胶质瘤的生长动力学， GSC的丰富，和的涌入，促进了疗法的发展 对抗这些机制以改善结果。