Cellular and Molecular Mechanisms of GBM Infiltration

GBM 浸润的细胞和分子机制

基本信息

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
项目类别：
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

项目摘要

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.

概括胶质母细胞瘤（GBM）是成人中最常见和致命的原发性脑肿瘤。其特点之一是 GBM 使其极其难以治愈的原因是其在整个大脑中的弥漫性浸润，作为治疗，包括原发肿瘤的手术切除总是会导致复发，通常远离原发部位原肿瘤。这一临床特征说明了 GBM 生物学的一个关键知识差距，因为细胞和驱动肿瘤细胞在大脑中迁移的分子机制仍然不明确。最近的研究表明 GBM 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动的增加会刺激 GBM 细胞向活跃的神经元迁移对侧半球。破译驱动活动依赖性 GBM 浸润的分子机制，我们对这些肿瘤进行了转录组分析，发现轴突引导基因的富集和显着的免疫相关特征的改变。轴突引导基因队列的功能研究表明小鼠 GBM 中 EphA6、EphA7 或 Sema4F 的过度表达促进肿瘤细胞浸润荷瘤小鼠的存活率降低。同样，我们发现 CD8-T 细胞响应活动而减少 - 驱动渗透和初步研究表明，这些群体的丧失会增强恶性程度进展。根据这些初步研究的强度，我们提出了三个具体目标，旨在揭示驱动 GBM 浸润的细胞和分子机制。在目标 1 中，我们将操纵神经元亚型，以剖析哪些神经元亚型促进 GBM 浸润。在目标2中，我们将确定 EphA6、EphA7 和 Sema4F 如何促进 GBM 浸润和病理生理学。在目标3中，我们将确定神经元活动如何影响免疫反应，同时确定 CD8 T 细胞如何影响免疫反应有助于 GBM 浸润。这些目标共同将揭示哪些神经元群促进 GBM 浸润，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。