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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.

脑肿瘤治疗中的一个主要问题是它们的侵袭性生长和侵入周围组织。正常脑组织。不幸的是，我们对攻击行为背后机制的理解这些肿瘤的数量非常有限。最近的证据表明，实体瘤的侵袭性涉及 Rho GTP酶下游的信号传导事件。Rho家族的小GTP酶一般和RhoA在特别是，是定向细胞迁移、细胞分裂和单层开放的关键调节剂。我们的基本关于细胞迁移机制的研究结果已经确定了Rho鸟嘌呤交换因子（GEF） Syx通过与Crumbs极性成员的相互作用，在促进定向细胞迁移中发挥重要作用复合物和RhoA信号传导的活化。有趣的是，Syx在人类神经胶质瘤中高度表达。初步研究表明，除了抑制细胞迁移外，Syx的缺失还严重损害了细胞的增殖。在GBM的异种移植小鼠模型中，抑制胶质瘤细胞分裂并显著改善动物存活。此外，抑制培养的神经胶质瘤细胞中的Syx信号传导与替莫唑胺（TMZ）强烈协同， GBM的标准治疗这个项目的总体科学前提是，Syx信号在其中起着重要的作用。在GBM细胞生长、迁移和侵袭以及对化疗药物的反应中起关键作用。作为因此，我们假设Syx-RhoA信号传导轴的治疗靶向可以抑制抑制人神经胶质瘤的侵袭性生长和侵袭，并与标准护理疗法协同作用。进一步表征Syx在人GBM的侵袭性生长和侵袭性中的作用，并测试其功效。靶向Syx信号传导与标准GBM治疗相结合，我们将使用培养的细胞，器官型人GBM的培养物、动物模型以及人GBM组织样品，以： 1.描述Syx耗竭对GBM攻击性的影响。 2.确定Syx-RhoA信号轴的关键组成部分。 3.确定抑制Syx是否可以增强化疗药物的疗效。