Molecular Mechanisms of Cell Invasion

细胞侵袭的分子机制

基本信息

批准号：
8710021
负责人：
CRISLYN D'SOUZA-SCHOREY
金额：
$ 27.17万
依托单位：
UNIVERSITY OF NOTRE DAME
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-25 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8710021
关键词：
Actins Actomyosin Address Adhesions Adhesives Area Ascites Biochemical Biogenesis Biology Blood Body Fluids Build-it Cell membrane Cell physiology Cell surface Cell-Cell Adhesion Cells Clinical Communication Cytoskeleton Deposition Diagnostic Disease Disease Progression Distal Down-Regulation Effectiveness Elements Environment Excision Extracellular Matrix Funding Goals Growth Factor Integrins Invaded Investigation Lead Life Location Malignant Neoplasms Mediating Mediator of activation protein Membrane Membrane Protein Traffic Metalloproteases Methods Molecular Myosin Light Chains Myosin Type II Neoplasm Metastasis Pathway interactions Peptide Hydrolases Phenotype Phosphorylation Population Primary Neoplasm Process Protein Family Proteins Proteolysis Recruitment Activity Recycling Regulation Research Resistance Signal Pathway Signal Transduction Site Sorting - Cell Movement Structure Surface Testing Therapeutic Therapeutic Intervention Tissues Tumor Biology Tumor Cell Biology Tumor Cell Invasion United States National Institutes of Health Urine Vesicle Work base cancer complication cancer diagnosis cell motility extracellular fascin insight interest member neoplastic cell paracrine particle receptor rho therapeutic target tumor

项目摘要

DESCRIPTION (provided by applicant): This is an application to investigate the mechanisms of microvesicle biogenesis in invasive tumor cells. It builds on exciting findings generated with previous NIH funding on a unique population of vesicles, called microvesicles that contain functionally active proteases and are released by tumor cells as they acquire invasive potential. The release of protease-loaded microvesicles may serve as a mechanism to bring about matrix degradation and perhaps even deposit paracrine information at distal locations, thus creating paths of "least resistance" as tumor cells invade and migrate through surrounding tissue. This is distinct from pericellular proteolysis at invadopodia, which enables localized matrix degradation juxtaposed to the leading edge. Discovering that there may exist more than one mode of proteolytic invasion, limits the effectiveness of any invasion-targeted therapeutic strategy that does not include both focal and distal proteolysis. While a significant amount of research has been directed to the understanding mechanisms of invadopodia formation and function at sites of cell invasion, microvesicles biogenesis and function remains a relatively understudied area of tumor biology. However, recent accruing evidence demonstrating the bona fide presence of microvesicles in body fluids (blood, urine and ascites), and their potential to serve as indicators of disease, has extended interest and intensified research efforts in microvesicle biology and function. The overarching objective of this application is to define molecular mechanisms of microvesicle formation. The project focuses on the central hypothesis that specific ARF and Rab proteins direct membrane type proteases and other proteins to sites of microvesicle biogenesis and that tight interchanges between RhoA and Rac1 signaling governs the plasticity required for switching between microvesicle and invadopodia-mediated proteolytic invasion. We will address two specific aims. In the first aim, we will define endocytic recycling pathways that direct cargo to sites of microvesicle biogenesis as well as examine how recruitment of specific Rab effectors regulate actomyosin-based contraction required for microvesicle biogenesis. In the second aim, we will examine the spatial activation of RhoA and Rac1 in invasive tumor cells. We will also investigate potential mechanisms that regulate Rac1 down regulation during microvesicle formation and how Rho signaling facilitates the process. Given recent heightened interest in the biology and clinical promise of microvesicles, these investigations are highly current. They will advance present understanding of microvesicle biogenesis and have potential to provide targets for diagnostic as well as therapeutic application.

描述（由申请人提供）：这是一项研究侵袭性肿瘤细胞中微泡生物发生机制的应用。它建立在美国国立卫生研究院之前资助的关于一种独特的囊泡群体的令人兴奋的发现之上，这种囊泡称为微囊泡，含有功能活性蛋白酶，并在肿瘤细胞获得侵袭潜力时由肿瘤细胞释放。负载蛋白酶的微泡的释放可能作为一种机制，引起基质降解，甚至可能在远端位置沉积旁分泌信息，从而在肿瘤细胞侵入和迁移通过周围组织时形成“最小阻力”的路径。这与侵袭伪足的细胞周蛋白水解不同，后者使得局部基质降解与前缘并列。发现可能存在不止一种蛋白水解侵袭模式，限制了任何不包括局部和远端蛋白水解的侵袭靶向治疗策略的有效性。虽然大量研究致力于了解细胞侵袭部位的侵袭伪足形成和功能的机制，但微泡的生物发生和功能仍然是肿瘤生物学中相对较少研究的领域。然而，最近越来越多的证据表明体液（血液、尿液和腹水）中确实存在微泡，及其作为疾病指标的潜力，这引起了人们对微泡生物学和功能的兴趣并加强了研究工作。本申请的首要目标是定义微泡形成的分子机制。该项目的重点是中心假设，即特定的 ARF 和 Rab 蛋白将膜型蛋白酶和其他蛋白引导至微泡生物发生位点，并且 RhoA 和 Rac1 信号之间的紧密互换控制着微泡和侵入伪足介导的蛋白水解入侵之间切换所需的可塑性。我们将解决两个具体目标。在第一个目标中，我们将定义将货物引导至微泡生物发生位点的内吞回收途径，并研究特定 Rab 效应器的募集如何调节微泡生物发生所需的基于肌动球蛋白的收缩。在第二个目标中，我们将检查侵袭性肿瘤细胞中 RhoA 和 Rac1 的空间激活。我们还将研究在微泡形成过程中调节 Rac1 下调的潜在机制以及 Rho 信号如何促进该过程。鉴于最近人们对微泡的生物学和临床前景的兴趣日益浓厚，这些研究非常流行。它们将增进目前对微泡生物发生的理解，并有可能为诊断和治疗应用提供靶点。