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

项目总结 恶性胶质瘤是一组高级别的脑肿瘤，代表了最常见的 恶性脑瘤。目前的治疗方案包括手术、化疗和 而放射治疗对最致命的胶质瘤变种多形性胶质母细胞瘤(GBM)的中位存活率尚未达到。 在确诊后仅仅15个月仍然停滞不前。当新的科学研究继续产生新的 疾病驱动机制，存活率在过去30年中保持不变，突显出 需要新的治疗方法来治疗这些一致致命的疾病。 长期以来，癌症生物学中发育范式的存在一直被认为是 促进肿瘤进展的失调的生物过程。除了发育生物学之外 癌症研究的方法，最近的科学研究表明，恶性胶质瘤形成 直接突触与瘤外神经元的电化学连接以维持持续的 扩散和迁徙。胶质瘤细胞与非肿瘤神经之间这种复杂相互作用的研究 Cells已经推出了一系列新的科学研究，被称为“癌症神经科学”。鉴于两者的存在 在这些发育和神经科学的先例中，我们建议调查发育如何 负责突触发生和突触维持的程序在恶性肿瘤中得到利用和维持 神经胶质瘤。 我们实验室发现了一种新的膜结合蛋白，免疫球蛋白超家族成员3 (IGSF3)，在子宫神经发育和恶性胶质瘤中均有高表达。上一首 研究表明IGSF3在发育中的大脑中控制神经元的形态发生，我们的初步研究 数据表明，它可能是一种新的胎儿癌基因，在这两种发育中的表达都显著增加 和恶性胶质瘤，但在出生后大脑中的表达很低。我们的初步研究使用的是子宫内的 电穿孔小鼠胶质瘤模型显示IGSF3过表达通过以下途径促进肿瘤进展 增加了增殖，降低了存活率。此外，IGSF3的过度表达会促进早发性 在肿瘤小鼠的癫痫发作中，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的增加推动了 通过破坏突触微环境和增加神经元的过度兴奋性而导致的恶性胶质瘤 周围的神经元回路。这种超兴奋性然后反馈给肿瘤，促进肿瘤的生长 通过增加有丝分裂和迁移信号通路的进展。在此，我们的研究建议 旨在总结之前报道的研究成果和我们的初步实验结果 支持我们的假设和理论基础，并旨在解释我们研究的意义和创新 作为我们将使用的科学方法和技术，以执行我们的科学研究路线。

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.