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）是成人原发性脑肿瘤的最常见和致命形式。一个特征使其难以治愈的GBM是其在整个大脑中的扩散浸润，作为治疗包括原发性肿瘤的手术切除总是会导致复发，通常远离原始肿瘤。该临床特征说明了GBM生物学的关键知识差距，作为细胞和驱动大脑肿瘤细胞迁移的分子机制仍然很差。最近的研究表明，GBM进展与神经元活性密切相关，我们的初步研究表明增加神经元活性会刺激GBM细胞向多动神经元的迁移对侧半球。破译分子机制驱动活性依赖性GBM浸润，我们对这些肿瘤进行了转录组分析，发现了轴突引导基因的富集和剧烈的免疫相关签名的改变。用轴突引导基因组的功能研究表明，小鼠GBM中EPHA6，EPHA7或SEMA4F的过表达促进了肿瘤细胞和肿瘤轴承小鼠的存活率降低。同样，我们发现响应于活性的CD8-TCELLS降低驱动的浸润和初步研究表明，这些人群的丧失会增强恶性进展。根据这些初步研究的优势，我们提出了三个试图发现的特定目标驱动GBM浸润的细胞和分子机制。在AIM 1中，我们将操纵神经元的子集为了剖析哪些亚类型神经元促进GBM浸润。在AIM2中，我们将确定EPHA6，EPHA7和SEMA4F如何有助于GBM浸润和病理生理学。在AIM3中，我们将确定神经元活性如何影响免疫反应，同时确定CD8 T细胞的方式有助于GBM浸润。这些目的共同发现了哪些神经元种群促进GBM 浸润，同时揭示了轴突引导基因和趋化因子受体的新作用病理生理学。