Glioma Circuitry: Bridging Systems Neuroscience and Cancer

项目摘要 高级别胶质瘤，如胶质母细胞瘤和弥漫性桥脑胶质瘤(DIPG)是主要的 成人和儿童脑癌相关死亡的原因。在人类最难治的癌症中， 这些肿瘤复发很快，几乎不可能根除。我们在方法上的根本转变 目前急需神经胶质瘤的治疗方法。我的研究小组最近发现，胶质瘤的生长是由于 神经系统活动以及神经胶质瘤对这些神经元表现出惊人的深度依赖 机械装置。我们的细胞和分子工作使我们惊人地认识到，胶质瘤在功能上 通过真正的神经元到胶质瘤突触整合到电激活的神经元电路中，以及 神经元到胶质瘤的信号可能通过最近描述的网络在整个肿瘤中被放大 胶质瘤到胶质瘤的缝隙连接介导的连接。我们假设这个合作的、相互关联的 胶质瘤细胞和神经元的网络是高级别胶质瘤进展和治疗耐药的基础。 因此，对这种致命的脑癌进行有效的治疗可能不仅需要靶向分子 细胞的增殖和存活机制，以及膜的去极化和结构模式 细胞之间的连接。为了研究这一点，从占主导地位的细胞/分子角度 从癌症生物学到系统神经科学的方法是必要的。在目前的建议中，我们寻求应用 现代系统神经科学的新一代强大工具与患者衍生的原位手术 高级别胶质瘤异种移植模型对高级别脑胶质瘤电路动力学的标测、监测和控制 在疾病过程中的进行性时间点的胶质瘤。神经活动的光遗传控制 清醒、行为状态下脑胶质瘤细胞膜去极化的电位和活体钙显像 小鼠将阐明胶质瘤回路活动的不同时间和空间模式的功能意义 神经胶质瘤的生长。分子干预旨在分解神经元的不同组成部分- 神经胶质瘤网络将辨别每种药物的相对贡献，并确定新的治疗靶点。最终， 治疗调节恶性回路活动可能证明对高级别胶质瘤具有转化性 结果。！

Project Summary High-grade gliomas, such as glioblastoma and diffuse intrinsic pontine glioma (DIPG), represent the leading cause of brain cancer-related death for both adults and children. Among the most intractable human cancers, these tumors are quick to recur and nearly impossible to eliminate. A fundamental shift in our approach to glioma therapy is in dire need. My research group has recently discovered that gliomas grow in response to nervous system activity and further that gliomas exhibit a surprisingly profound dependency on these neuronal mechanisms. Our cellular and molecular work has led us to the startling realization that gliomas functionally integrate into electrically active neuronal circuits through bona fide neuron to glioma synapses, and the effects of neuron to glioma signaling may be amplified throughout the tumor via a network of recently described glioma to glioma gap junction-mediated connections. We hypothesize that this cooperative, interconnected network of glioma cells and neurons is fundamental to high-grade glioma progression and therapy resistance. Effective therapy for this lethal group of brain cancers may therefore require targeting not only molecular mechanisms of cell proliferation and survival, but also patterns of membrane depolarization and structural connections between cells. In order to study this, a shift from the predominant cellular/molecular perspective of cancer biology to a systems neuroscience approach is required. In the present proposal, we seek to apply the powerful next-generation tools of modern systems neuroscience together with patient-derived orthotopic xenograft models of high-grade gliomas to map, monitor and control the circuit dynamics of high-grade gliomas at progressive time points during the course of the disease. Optogenetic control of neuronal action potentials and of glioma membrane depolarizations together with live calcium imaging in awake, behaving mice will elucidate the functional significance of various temporal and spatial patterns of glioma circuit activity to glioma growth. Molecular interventions aimed at disassembling the various components of the neuronal- glioma network will discern the relative contribution of each and identify novel therapeutic targets. Ultimately, therapeutically modulating malignant circuit activity may prove transformative for high-grade glioma outcomes.!