Cellular and Molecular Mechanisms of GBM Infiltration

GBM 浸润的细胞和分子机制

• 批准号: 10383061
• 负责人: Benjamin Deneen
• 金额: $ 45.44万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-15 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10383061
• 关键词: Adult; Automobile Driving; Biology; Brain; Brain Neoplasms; CD8-Positive T-Lymphocytes; CD8B1 gene; Cells; Chemotherapy and/or radiation; Clinical; Contralateral; Corpus Callosum; Diagnosis; Diffuse; Disease; Excision; Functional disorder; Gene Expression; Gene Mutation; Genes; Glioblastoma; Goals; Hyperactivity; Immune; Immune response; Infiltration; Journals; Knock-out; Knowledge; Laboratories; Link; Malignant - descriptor; Modeling; Molecular; Mus; Nature; Neoplasm Metastasis; Neurons; Operative Surgical Procedures; Pathogenesis; Play; Population; Primary Brain Neoplasms; Primary Neoplasm; Recurrence; Role; Site; Survival Rate; Tumor Cell Migration; axon guidance; base; brain parenchyma; chemokine receptor; clinical investigation; cohort; excitatory neuron; genetic manipulation; human disease; inhibitory neuron; migration; mortality; mouse model; neoplastic cell; novel; novel therapeutic intervention; overexpression; response; single-cell RNA sequencing; transcriptomics; tumor; tumorigenesis; white matter

Summary Glioblastoma (GBM) is the most common and deadly form of primary brain tumor in adults. One feature of GBM that makes it exceedingly difficult to cure is its diffuse infiltration throughout the brain, as treatment, including surgical resection of the primary tumor invariably results in recurrence, often remote from the site of the original tumor. This clinical feature illustrates a key knowledge gap in GBM biology, as the cellular and molecular mechanisms that drive the migration of tumor cells in the brain remain poorly defined. Recent studies have shown that GBM progression is tightly linked to neuronal activity and our preliminary studies show that increased neuronal activity stimulates migration of GBM cells towards hyperactive neurons in the contralateral hemisphere. To decipher the molecular mechanisms driving activity-dependent, GBM infiltration, we performed transcriptomic analysis of these tumors, finding enrichment of axon guidance genes and drastic alterations in immune-related signatures. Functional studies with the axon guidance gene cohort revealed that overexpression of EphA6, EphA7, or Sema4F in mouse GBM promoted infiltration of tumor cells and decreased survival of tumor bearing mice. Similarly, we found decreased CD8-Tcells in response to activity- driven infiltration and preliminary studies suggest that loss of these populations enhances malignant progression. Based on the strength of these preliminary studies we propose three specific aims that seek to uncover the cellular and molecular mechanisms driving GBM infiltration. In aim 1, we will manipulate the activity of subsets of neurons in order to dissect which sub-types of neurons promote GBM infiltration. In aim2, we will determine how EphA6, EphA7, and Sema4F contribute to GBM infiltration and pathophysiology. In aim3, we will determine how neuronal activity influences immune responses, while determining how CD8 T-cells contribute to GBM infiltration. Together, these aims will uncover which neuronal populations promote GBM infiltration, while revealing new roles for axon guidance genes and chemokine receptors in tumor pathophysiology.

摘要 胶质母细胞瘤(GBM)是成人最常见、最致命的原发脑肿瘤。的一个特点是 基底膜非常难以治愈的是它在大脑中的弥漫性渗透，作为治疗， 包括手术切除原发肿瘤总是会导致复发，通常远离肿瘤的部位 原来的肿瘤。这一临床特征说明了基底膜生物学中的一个关键知识缺口，因为细胞和 驱动肿瘤细胞在大脑中迁移的分子机制仍不清楚。近期 研究表明，基底膜的进展与神经元活动密切相关，我们的初步研究表明 神经元活性增加刺激基底膜细胞向高活性神经元迁移 对侧半球。为了破译驱动活性依赖的基底膜渗透的分子机制， 我们对这些肿瘤进行了转录转录分析，发现轴突引导基因和DRASTIC丰富 免疫相关特征的改变。轴突引导基因队列的功能研究表明 EphA6、EphA7或Sema4F在小鼠GBM中的过表达促进肿瘤细胞的侵袭和 降低荷瘤小鼠的存活率。同样，我们发现CD8-T细胞对活动的反应减少- 被驱使的渗透和初步研究表明，这些人口的丧失会加剧恶性 进步。 基于这些初步研究的力量，我们提出了三个具体目标，试图揭示 基底膜浸润的细胞和分子机制。在目标1中，我们将操纵 为了解剖哪些神经元亚型促进了基底膜的渗透。在AIM2中，我们将 确定EphA6、EphA7和Sema4F如何促进基底膜的渗透和病理生理学。在AIM 3中，我们 将决定神经元活动如何影响免疫反应，同时决定CD8 T细胞如何 有助于GBM的渗透。综合起来，这些目标将揭示哪些神经元群体促进了基底膜 渗透，同时揭示轴突引导基因和趋化因子受体在肿瘤中的新作用 病理生理学。