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

脑肿瘤治疗中的一个主要问题是它们的侵袭性生长和对周围的侵袭。 正常的脑组织。不幸的是，我们对攻击性行为背后机制的理解 这些肿瘤的数量是非常有限的。最近的证据表明，实体肿瘤的侵袭性包括 Rho GTP酶下游的信号事件。Rho家族中的小GTP酶和RhoA 尤其是定向细胞迁移、细胞分裂和单层通透性的关键调节因子。我们的基础 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 Syx通过与Crumbs极性成员的相互作用，在促进细胞定向迁移方面发挥重要作用 复合体，并激活RhoA信号。有趣的是，Syx在人脑胶质瘤中高度表达。 初步研究表明，Syx的耗尽除了抑制细胞迁移外，还会严重损害 在胶质瘤细胞分裂，并显著提高动物存活率的异种移植小鼠模型的GBM。 此外，抑制培养的胶质瘤细胞中的Syx信号与替莫唑胺(TMZ)有很强的协同作用。 GBM的护理治疗标准。这个项目的总体科学前提是Syx信令扮演着 在基底膜细胞的生长、迁移和侵袭以及对化疗药物的反应中起关键作用。AS 因此，我们假设针对Syx-RhoA信号轴的治疗性靶向可以抑制 人类胶质瘤的侵袭性生长和侵袭性，并与标准护理治疗协同作用。为了进一步 鉴定Syx在人GBM侵袭性生长和侵袭性中的作用并测试其有效性 结合标准的GBM治疗靶向Syx信号，我们将使用培养细胞，器官型 培养人基底膜的动物模型，以及人基底膜组织样本，以： 1.表征Syx耗竭对GBM侵袭性的影响。 2.确定Syx-RhoA信号轴的关键组件。 3.确定抑制Syx是否能增强化疗药物的疗效。

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.