SNARE-Mediated Exocytosis in Migration of Pancreatic Cancer Cells

SNARE 介导的胰腺癌细胞迁移中的胞吐作用

基本信息

批准号：
7846594
负责人：
Chuan Hu
金额：
$ 1.83万
依托单位：
UNIVERSITY OF LOUISVILLE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-06-01 至 2009-10-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Pancreatic cancer is the fourth leading cause of cancer death in the United States. Metastasis - the spreading of cancer from a primary site to distant organs is responsible for 90 percent of the deaths from pancreatic cancer. A fundamental event in metastasis is the migration of cancer cells. Accumulating evidence indicates that intracellular vesicle trafficking plays an important role in cell migration. In migrating cells, plasma membrane components and cell adhesion receptors such as integrins are transported by vesicles and exocytosed at the cell front or leading edge. However, it is not known what proteins drive polarized exocytosis and how exocytosis is modulated in cancer metastasis. Studies using model systems has demonstrated that pairing of SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins on vesicles (v-SNAREs) and SNARE proteins on target membrane (t-SNAREs) mediates intracellular vesicle fusion events including exocytosis. Our preliminary studies indicate that SNARE proteins are actively involved in cell migration. The hypothesis is that SNARE proteins mediate polarized exocytosis in migration of pancreatic cancer cells. Using cell-based assays, two Specific Aims will be pursued: 1) Define the function of endocytic v-SNAREs in migration of pancreatic cancer cells; 2) Identify v-SNAREs that mediate the recycling of ?1 integrins to the cell surface. The long-term goal is to elucidate how the SNARE fusion machinery interacts with signal transduction cascades to regulate migration and metastasis of pancreatic cancer cells. Accomplishing the specific aims will deepen our understanding of polarized exocytosis in cell migration, and will likely provide potential targets for therapeutic strategies that target motility of pancreatic cancer cells. PUBLIC HEALTH RELEVANCE: Cancer metastasis is still not well understood at the molecular level, and current therapies are ineffective in preventing metastasis. Inhibiting the migration of cancer cells is a promising strategy to overcome metastasis. The proposed work will enhance our understanding of the most fundamental event in metastasis - migration of cancer cells.

描述（由申请人提供）：胰腺癌是美国癌症死亡的第四个主要原因。转移 - 癌症从主要部位传播到远处的器官是胰腺癌死亡的90％。转移的基本事件是癌细胞的迁移。积累的证据表明，细胞内囊泡运输在细胞迁移中起重要作用。在迁移的细胞中，质膜成分和细胞粘附受体（如整联蛋白）通过囊泡运输，并在细胞前边缘或前缘外旋转。然而，尚不知道哪些蛋白质驱动了两极化的胞吐作用以及如何在癌症转移中调节胞吐作用。使用模型系统的研究表明，在囊泡（V-SNARES）（v-sNARES）和靶膜上介导细胞内囊泡融合事件的囊泡（V-SNARES）和SNARE蛋白上的SNARE（可溶性N-乙基甲米酰胺敏感因子附着蛋白受体）蛋白的配对。我们的初步研究表明，网罗蛋白积极参与细胞迁移。假设是，在胰腺癌细胞的迁移中，网罗蛋白介导了两极化的胞吐作用。使用基于细胞的测定法，将追求两个具体目标：1）定义内吞V-snARES在胰腺癌细胞迁移中的功能； 2）识别介导1个整联蛋白回收到细胞表面的v-snares。长期的目标是阐明圈套融合机械如何与信号转导级联相互作用以调节胰腺癌细胞的迁移和转移。实现具体目标将加深我们对细胞迁移两极分化胞吐作用的理解，并可能为靶向胰腺癌细胞运动性的治疗策略提供潜在的靶标。公共卫生相关性：在分子水平上，癌症转移仍然不太了解，并且当前的疗法在预防转移方面无效。抑制癌细胞的迁移是克服转移的有前途的策略。拟议的工作将增强我们对癌细胞转移迁移最基本事件的理解。