Regulation of cell migration by septin 2 in renal cancer

项目摘要 肾细胞癌（Renal cell carcinoma，RCC）是一种侵袭性强、转移性高的恶性肿瘤 国际吧40%的局限性RCC患者显示肿瘤复发和进展。患者 晚期肾细胞癌对治疗干预的反应较差，只有10%的患者在诊断后存活5年。在 在所有肾癌中，超过一半的von-Hippel Lindau肿瘤抑制因子是有缺陷的， Septin 2（SEPT 2）的上调，Septin 2是GTP酶的Septin家族的成员。Septins在进化上是相关的 Ras癌基因，并被用作结肠直肠癌和泌尿系统癌症的生物标志物。迄今为止， 目前尚不清楚septins在RCC进展和转移中的作用。初步数据显示， SEPT 2是RCC迁移和细胞外基质（ECM）粘着斑组装所必需的， 这对于定向持久迁移是必要的。我们假设SEPT 2促进RCC迁移， 通过调节肌动蛋白应力纤维在RCC-基质粘附位点的组装和组织。这里我们 将探讨这一假说的机制原则，并测试Septin GTP酶作为RCC的治疗靶点 转移具体而言，该项目旨在：i）确定SEPT 2在局部粘连组装中的作用 ii）鉴定SEPT 2调节肌动蛋白应力纤维组织的机制 iii）检查SEPT 2表达的改变和药理学靶向如何影响 RCC在模拟体内肿瘤微环境的三维（3D）基质中的运动性。这些目标将 通过Septin生物学领域的主要研究人员的协作指导计划实现， 肌动蛋白细胞骨架和癌细胞迁移。拟议中的研究计划涉及尖端技术的培训， 光学和电子显微镜的方法，以及组织培养的3D模型。课程，会议， 演讲和写作活动将确保细胞迁移和翻译基础知识的培训 癌症研究。总之，该项目将为SEPT 2在RCC迁移中的作用提供新的见解 以及SEPT 2靶向方法治疗RCC转移的有效性，这为我们提供了一种新的方法， 癌症细胞生物学的独立职业。

Project Summary Renal cell carcinoma (RCC) is an aggressive and highly metastatic cancer with rising incidence worldwide. Forty percent of patients with localized RCC show tumor recurrence and progression. Patients with advanced RCC respond poorly to therapeutic intervention and only 10% survive five years past diagnosis. In more than half of all renal cancers, the von-Hippel Lindau tumor suppressor is defective leading to the upregulation of septin 2 (SEPT2), a member of the septin family of GTPases. Septins are evolutionarily related to the Ras oncogenes and are being used as biomarkers for colorectal and urological cancers. To date, it is completely unknown how septins function in RCC progression and metastasis. Our preliminary data show that SEPT2 is required for RCC migration and the assembly of focal adhesions to the extracellular matrix (ECM), which is essential for directionally persistent migration. We hypothesize that SEPT2 promotes RCC migration by regulating the assembly and organization of actin stress fibers at sites of RCC-matrix adhesion. Here, we will explore mechanistic tenets of this hypothesis and test septin GTPases as therapeutic targets for RCC metastasis. Specifically, this project aims to: i) determine the role of SEPT2 in the assembly of focal adhesions with the ECM, ii) identify the mechanism by which SEPT2 regulates the organization of the actin stress fiber network of RCCs, and iii) examine how alterations and pharmacological targeting of SEPT2 expression affect RCC motility in three-dimensional (3D) matrices that mimic in vivo tumor microenvironments. These aims will be achieved through a collaborative mentoring program by leading investigators in the areas of septin biology, actin cytoskeleton and cancer cell migration. The proposed research plan involves training in cutting edge methodologies of light and electron microscopy, and 3D models of tissue culture. Courses, conferences, speaking and writing engagements will ensure training in the fundamentals of cell migration and translational cancer research. In summary, this project will provide a novel insight into the role of SEPT2 in RCC migration and the efficacy of SEPT2-targeted approaches for the treatment of RCC metastasis, leading the way to an independent career in cancer cell biology.