Role of the Syx-RhoA signaling axis in glioma cell growth and dissemination

Syx-RhoA 信号轴在神经胶质瘤细胞生长和传播中的作用

基本信息

批准号：
9923013
负责人：
Panagiotis Z. Anastasiadis
金额：
$ 34.28万
依托单位：
MAYO CLINIC JACKSONVILLE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-05-15 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9923013
关键词：
Ablation Actins Affect Aggressive behavior Animal Model Animals Apoptosis Basic Science Binding Blood - brain barrier anatomy Blood Vessels Brain Brain Neoplasms Cell Adhesion Cell Cycle Progression Cell Polarity Cell division Cells Central Nervous System Neoplasms Clinical Complex Coupled Couples Cultured Cells Cytoskeleton Diffuse Effectiveness Endothelial Cells Etiology Event Excision Exhibits Extracellular Matrix Family Gene Expression Genetic Glioblastoma Glioma Growth Guanine Guanine Nucleotide Exchange Factors Human Impairment In Vitro Intervention Knockout Mice Link Malignant Glioma Malignant Neoplasms Mechanics Mediating Monomeric GTP-Binding Proteins Morphology Mus Nature Nuclear Outcome PLEKHG5 gene Pathway interactions Penetrance Penetration Permeability Pharmaceutical Preparations Pharmacology Play Radiation Research Role Signal Transduction Solid Neoplasm Testing Therapeutic Therapeutic Intervention Tissue Sample U251 Vascular Permeabilities Xenograft procedure angiogenesis brain endothelial cell brain tissue cancer cell cell growth cell motility chemotherapy efficacy testing egg human model improved in vivo insight knock-down member migration monolayer mortality mouse model neoplastic cell novel rapid growth response rho rho GTP-Binding Proteins standard of care targeted treatment temozolomide therapeutic target tumor tumor behavior

项目摘要

A major issue in the management of brain tumors is their aggressive growth and invasion into surrounding normal brain tissue. Unfortunately, our understanding of the mechanisms that underlie the aggressive behavior of these tumors is very limited. Recent evidence indicates that the invasiveness of solid tumors involves signaling events downstream of Rho GTPases. The Rho family of small GTPases in general and RhoA in particular, are critical regulators of directed cell migration, cell division, and monolayer patency. Our basic research findings on the mechanics of cell migration have identified the Rho guanine exchange factor (GEF) Syx as important in promoting directed cell migration, via its interaction with members of the Crumbs polarity complex, and activation of RhoA signaling. Interestingly, Syx is highly expressed in human gliomas. Preliminary studies show that in addition to suppressing cell migration, depletion of Syx drastically impairs glioma cell division, and significantly improves animal survival in a xenograft mouse model of GBM. Additionally, inhibition of Syx signaling in cultured glioma cells strongly synergizes with Temozolomide (TMZ), the standard of care therapy for GBM. The overall scientific premise of this project is that Syx signaling plays a key role in GBM cell growth, migration and invasion, as well as in responsiveness to chemotherapeutics. As such, we hypothesize that therapeutic targeting of the Syx-RhoA signaling axis can suppress both the aggressive growth and invasion of human gliomas and synergize with standard-of-care therapy. To further characterize the role of Syx in the aggressive growth and invasiveness of human GBM and to test the efficacy of targeting Syx signaling in combination with standard GBM therapy, we will use cultured cells, organotypic cultures, animal models of human GBM, as well as human GBM tissue samples, to: 1. Characterize the effect of Syx depletion on GBM aggressiveness. 2. Identify key components of the Syx-RhoA signaling axis. 3. Determine whether inhibition of Syx can enhance the efficacy of chemotherapeutics.

脑肿瘤管理的主要问题是它们的侵略性生长和入侵周围正常的脑组织。不幸的是，我们对侵略行为基础机制的理解这些肿瘤非常有限。最近的证据表明，实体瘤的侵入性涉及 Rho GTPases下游的信号事件。一般的小gtpases的Rho家族和Rhoa 特别是定向细胞迁移，细胞分裂和单层通畅的关键调节因子。我们的基本关于细胞迁移力学的研究结果已经确定了Rho Guanine交换因子（GEF） Syx通过与碎屑成员的相互作用而在促进定向细胞迁移方面很重要复合物和RhoA信号的激活。有趣的是，Syx在人神经膜瘤中高度表达。初步研究表明，除了抑制细胞迁移外，Syx的耗竭会急剧损害神经胶质瘤细胞分裂，并在GBM的异种移植小鼠模型中显着提高了动物存活率。另外，抑制SYX信号在培养的神经胶质瘤细胞中与替莫唑胺（TMZ）强烈协同的抑制作用， GBM的护理疗法标准。该项目的总体科学前提是Syx信号发挥 GBM细胞生长，迁移和侵袭以及对化学治疗剂的反应中的关键作用。作为这样，我们假设SYX-RHOA信号轴的治疗靶向可以抑制人神经胶质瘤的积极生长和入侵与护理标准疗法协同作用。进一步表征SYX在人类GBM的侵略性增长和侵入性中的作用并测试功效与标准GBM治疗结合使用SYX信号传导的靶向，我们将使用培养的细胞，器官型培养物，人类GBM的动物模型以及人类GBM组织样品， 1。表征SYX耗竭对GBM侵略性的影响。 2。确定SYX-RHOA信号轴的关键组件。 3。确定SYX的抑制是否可以增强化学治疗疗法的功效。