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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.

项目总结