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IGSF3 promotes tumor progression through synaptic remodeling and hyperexcitability in malignant glioma

IGSF3通过恶性神经胶质瘤的突触重塑和过度兴奋促进肿瘤进展

基本信息

批准号：
10315147
负责人：
Rachel Naomi Curry
金额：
$ 4.6万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10315147
关键词：
Affect Automobile Driving Back Bar Codes Behavior Binding Binding Proteins Bioinformatics Biological Assay Biological Process Brain Brain Neoplasms Bromodeoxyuridine CRISPR/Cas technology Cancer Biology Cell Communication Cell Cycle Cells Co-Immunoprecipitations Complex Data Development Developmental Biology Diagnosis Disease Disease Progression Electroencephalography Electrophysiology (science)Electroporation Excitatory Synapse Feeds Genes Glioblastoma Glioma Goals Growth Hematoxylin and Eosin Staining Method Histopathology Human Immunofluorescence Immunologic Immunoglobulins Impairment In Situ In Vitro Inhibitory Synapse Investigation Laboratories Lead Maintenance Malignant - descriptor Malignant Glioma Malignant Neoplasms Malignant neoplasm of brain Malignant neoplasm of central nervous system Maps Mass Spectrum Analysis Membrane Membrane Proteins Methodology Modeling Monitor Morphogenesis Mus Neuroepithelial, Perineurial, and Schwann Cell Neoplasm Neurons Neurosciences Oncogenes Oncogenic Operative Surgical Procedures Pathway interactions Patients Play Potassium Potassium Channel Proteomics Radiation therapy Reporting Research Research Proposals Role Sampling Scientific Inquiry Seizures Side Signal Pathway Slice Source Structure Survival Rate Synapses Techniques Testing Tissue Microarray Transposase Treatment Protocols Tumor Biology Tumor Tissue Variant anticancer research base early onset experimental study fetal gain of function glioma cell line in utero in vivo innovation loss of function member migration mouse model neoplastic cell neurodevelopment neuronal circuitry novel novel therapeutic intervention overexpression postnatal postsynaptic preservation presynaptic programs survival outcome synaptogenesis transcriptome sequencing transcriptomics tumor tumor progression

项目摘要

PROJECT SUMMARY Malignant gliomas are a group of high-grade brain neoplasms that represent the most common form of malignant brain tumors. Current treatment regimens include an amalgamation of surgical, chemotherapeutic and radiation treatments yet median survival for the most lethal glioma variant, glioblastoma multiforme (GBM) remains stagnant at a mere 15 months post-diagnosis. While new scientific inquiries continue to yield novel disease-driving mechanisms, survival rates have remained unchanged over the past 30 years, highlighting a need for new therapeutic approaches for these uniformly fatal diseases. The existence of developmental paradigms in cancer biology has long been established as a source of dysregulated biological processes that facilitate tumor progression. In addition to developmental biology approaches in cancer research, recent scientific investigations have revealed that malignant gliomas form direct synaptic electrochemical connections with extratumoral neurons in order to sustain continued proliferation and migration. The study of this complex interplay between glioma cells and non-tumor neural cells has launched a new line of scientific inquiry known as “cancer neuroscience”. Given the existence of both of these developmental and neuroscientific precedents, we propose to investigate how developmental programs responsible for synaptogenesis and synaptic maintenance are utilized and sustained in malignant glioma. Our laboratory has identified a novel membrane-bound protein, immunoglobulin superfamily member 3 (IGSF3), with high expression levels in both in utero neurodevelopment and malignant glioma. Previous studies have shown that IGSF3 controls neuronal morphogenesis in the developing brain and our preliminary data suggests it may serve as a novel fetal oncogene with markedly increased expression in both development and malignant glioma but minimal expression in the postnatal brain. Our preliminary studies using an in utero electroporation mouse model of glioma have revealed that IGSF3 overexpression drives tumor progression by increasing proliferation and decreasing survival. Furthermore, overexpression of IGSF3 promotes early-onset seizures in tumor mice and selectively increases excitatory presynaptic and postsynaptic components at the tumor margin. Based on our initial studies, we have hypothesized that increased IGSF3 drives progression of malignant glioma by disrupting the synaptic microenvironment and increasing hyperexcitability in the surrounding neuronal circuitry. This hyperexcitability then feeds back to the tumor to promote tumor progression through increased mitogenic and promigratory signaling pathways. Herein, our research proposal seeks to summarize previously reported research findings and our preliminary experimental results that support our hypothesis and rationale, and aims to explain the significance and innovation of our study as well as the scientific methodologies and techniques we will utilize in order to execute our lines of scientific inquiry.

项目概要恶性胶质瘤是一组高级别脑肿瘤，代表最常见的形式恶性脑肿瘤。目前的治疗方案包括手术、化疗相结合和放射治疗，但最致命的胶质瘤变异——多形性胶质母细胞瘤（GBM）的中位生存期诊断后仅 15 个月仍处于停滞状态。虽然新的科学探究不断产生新颖的成果疾病驱动机制，生存率在过去 30 年中保持不变，突显了需要新的治疗方法来治疗这些致命的疾病。癌症生物学中发展范式的存在早已被确立为失调的生物过程促进肿瘤进展。除了发育生物学癌症研究方法，最近的科学研究表明，恶性胶质瘤形成与肿瘤外神经元的直接突触电化学连接，以维持持续的扩散和迁移。神经胶质瘤细胞与非肿瘤神经细胞之间复杂相互作用的研究细胞启动了一条新的科学探究路线，称为“癌症神经科学”。鉴于两者的存在在这些发育和神经科学先例中，我们建议研究发育如何负责突触发生和突触维持的程序在恶性疾病中得到利用和维持神经胶质瘤。我们的实验室鉴定出一种新型膜结合蛋白，免疫球蛋白超家族成员3 (IGSF3)，在子宫神经发育和恶性神经胶质瘤中都有高表达水平。以前的研究表明 IGSF3 控制发育中大脑的神经元形态发生，我们的初步研究表明数据表明它可能作为一种新的胎儿癌基因，在发育和发育过程中表达显着增加和恶性神经胶质瘤，但在出生后大脑中表达极少。我们的初步研究使用子宫内神经胶质瘤的电穿孔小鼠模型表明，IGSF3 过表达通过以下方式驱动肿瘤进展：增加增殖并降低存活率。此外，IGSF3的过度表达促进早发肿瘤小鼠的癫痫发作并选择性地增加兴奋性突触前和突触后成分肿瘤边缘。根据我们的初步研究，我们假设 IGSF3 的增加会导致疾病进展恶性神经胶质瘤通过破坏突触微环境并增加神经元的过度兴奋性周围的神经元电路。这种过度兴奋然后反馈给肿瘤，促进肿瘤生长通过增加有丝分裂和前迁移信号通路来进展。在此，我们的研究计划旨在总结之前报道的研究结果和我们的初步实验结果支持我们的假设和基本原理，并旨在解释我们研究的意义和创新作为我们用来执行科学探究的科学方法和技术。