Regulation of cell migration by septin 2 in renal cancer

项目摘要 摘要肾细胞癌是一种侵袭性强、转移性强的癌症，其发病率呈上升趋势。 全世界。40%的局限性肾细胞癌患者肿瘤复发和进展。患有疾病的患者 晚期肾癌对治疗干预的反应很差，只有10%的人在确诊后存活了五年。在……里面 在所有肾癌中，超过一半的冯-希佩尔·林道肿瘤抑制基因存在缺陷，导致 Septin 2(SEPT2)上调，SEPT2是GTP酶的Septin家族成员之一。几丁质在进化上是相关的 Ras癌基因，并被用作结直肠癌和泌尿系癌症的生物标记物。迄今为止，它是 完全不知道间隔蛋白在肾癌进展和转移中的作用。我们的初步数据显示， SEPT2是RCC迁移和与细胞外基质(ECM)组装焦点黏附所必需的， 这对于定向持续迁移是必不可少的。我们假设SEPT2促进RCC迁移 通过调节肌动蛋白应激纤维在RCC-基质粘连部位的组装和组织。在这里，我们 我将探索这一假说的机制原理，并测试Septin GTP酶作为肾癌的治疗靶点 转移。具体地说，这个项目的目的是：i)确定SEPT2在焦点粘连组装中的作用 通过ECM，II)确定SEPT2调节肌动蛋白应激纤维组织的机制 RCC网络，以及iii)研究SEPT2表达的改变和药理学靶向如何影响 模拟体内肿瘤微环境的三维(3D)矩阵中的RCC运动性。这些目标将 通过一个由Septin生物学领域的领先研究人员合作的指导计划来实现， 肌动蛋白细胞骨架与癌细胞迁移。拟议的研究计划涉及尖端技术培训。 光学显微镜和电子显微镜的方法学，以及组织培养的3D模型。课程、会议、 演讲和写作活动将确保培训细胞迁移和翻译的基础知识 癌症研究。总而言之，该项目将为SEPT2在RCC迁移中的作用提供一个新的见解 而SEPT2靶向治疗肾癌转移的有效性，导致了 独立从事癌细胞生物学研究。

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.