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

基本信息

批准号：
10394722
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
项目类别：
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/10394722
关键词：
3-Dimensional Animal Model Animals Attenuated Automobile Driving Biological Brain Brain Neoplasms CCAAT-Enhancer-Binding Proteins 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 Infiltrative Growth Investigation Label Lasers Lead Link Literature Malignant - descriptor Malignant Neoplasms Malignant neoplasm of brain Mesenchymal Methods Microscope Microscopic Modeling Molecular Mus Mutation NF1 mutation Necrosis PDGFB gene Patients Pattern Phase Primary Brain Neoplasms Process Property Radial Radial Growth Phase Recurrence Role Rose Bengal Sampling Signal Transduction TP53 gene Textbooks Therapeutic Therapeutic Intervention Thrombosis Time Tumor Cell Migration Tumor Expansion Tumor-Derived Tumor-associated macrophages Up-Regulation Vascular blood supply Xenograft procedure angiogenesis antagonist base 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 spatiotemporal stem cells stemness targeted treatment therapeutic target therapeutically effective therapy development therapy resistant thrombotic time use translational applications tumor tumor growth tumor microenvironment tumorigenic

项目摘要

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被动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在挑战。在胶质母细胞瘤（GBM；谁 IV级），最恶性的原发性脑肿瘤，这是快速，径向生长阶段在中央坏死的发展之前，迅速导致死亡。虽然GBM的遗传改变是广为人知的，但生物学特性由于他们的获取并导致这种加速增长阶段所致需要更深入调查。肿瘤微环境（TME）随后发生了巨大变化坏死的发作，来自浸润细胞的薄片样生长，相对恒定高度复杂且不断发展的3-D微系统组成的生长特性各种细胞类型和空间隔离的信号网络。更好地了解我们提出的动态时间和空间变化，我们建议在人神经胶质瘤中与这些事件紧密平行的预先鼠标模型，因为许多 GBM的小鼠模型缺乏坏死。我们开发了一种新颖的方法来诱导焦点高级神经胶质瘤内的坏死，将研究TME重组及其使用多光子显微镜实时对神经胶质瘤生长的影响。作为翻译应用，我们将证明缺氧和坏死如何促进神经胶质瘤干细胞（GSC）在其周围的细菌壁基中，并导致急剧流入肿瘤相关的巨噬细胞（TAM），数量在10倍以上增加人类疾病。我们提出了均具有遗传特征的患者衍生的GBM 具有人源性免疫细胞的小鼠生长的异种移植物以及免疫能力的RCAS/TV-A模型，并将确定它们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学表明，与新生儿胶质瘤之间存在实质性差异关于GSC和TAM富集及其对生物特性的影响，但机理和进化尚未深入研究，这在很大程度上是由于缺乏可靠的动物模型。我们的模型将捕获神经胶质瘤生长动态， GSC富集和TAM涌入，并促进疗法的发展拮抗这些机制以改善结果。