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

项目摘要 恶性神经胶质瘤是一组高级别脑肿瘤，其代表最常见的脑胶质瘤形式。 恶性脑瘤目前的治疗方案包括手术、化疗、化疗和化疗的结合。 而最致命的胶质瘤变体多形性胶质母细胞瘤（GBM）的中位生存期 在诊断后仅仅15个月就停滞不前。虽然新的科学研究继续产生新的 疾病驱动机制，生存率在过去30年中保持不变，突出了 需要新的治疗方法来治疗这些致命的疾病。 癌症生物学中的发育范式的存在长期以来一直被确立为癌症的起源。 促进肿瘤进展的失调的生物过程。除了发育生物学 在癌症研究的方法，最近的科学调查表明，恶性胶质瘤的形式， 直接与肿瘤外神经元的突触电化学连接，以维持持续的 扩散和迁移。胶质瘤细胞和非肿瘤神经细胞之间复杂相互作用的研究 cells发起了一项新的科学研究，被称为“癌症神经科学”。鉴于两者的存在 这些发展和神经科学的先例，我们建议调查如何发展 负责突触发生和突触维持的程序在恶性肿瘤中被利用和维持。 胶质瘤 我们的实验室已经确定了一种新的膜结合蛋白，免疫球蛋白超家族成员3 IGSF 3在子宫内神经发育和恶性胶质瘤中都有高表达。先前 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，在两种发育过程中表达显著增加， 和恶性胶质瘤，但在出生后的脑中表达很少。我们的初步研究是在子宫内 神经胶质瘤的电穿孔小鼠模型揭示IGSF3过表达通过以下方式驱动肿瘤进展： 增加增殖和降低存活率。此外，IGSF 3的过表达促进早发性 癫痫发作，并选择性地增加兴奋性突触前和突触后成分在肿瘤小鼠。 肿瘤边缘基于我们最初的研究，我们假设IGSF 3的增加会驱动肿瘤的进展。 通过破坏突触微环境和增加神经元的过度兴奋性， 周围的神经回路。这种过度兴奋然后反馈到肿瘤，以促进肿瘤生长。 通过增加促有丝分裂和促迁移信号通路的进展。在此，我们的研究建议 试图总结以前报道的研究结果和我们的初步实验结果， 支持我们的假设和理论基础，并旨在说明我们研究的意义和创新 我们将利用科学方法和技术来执行我们的科学探索路线。

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.