Molecular Mechanisms of Cell Invasion

细胞侵袭的分子机制

• 批准号: 8328697
• 负责人: CRISLYN D'SOUZA-SCHOREY
• 金额: $ 28.01万
• 依托单位: UNIVERSITY OF NOTRE DAME
• 依托单位国家: 美国
• 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/8328697
• 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

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）：这是研究浸润性肿瘤细胞中微泡生物发生机制的应用。它建立在以前的NIH资金上产生的令人兴奋的发现，这些发现在独特的囊泡中，称为含有功能活性蛋白酶的微泡，并在肿瘤细胞获得侵入性潜力时释放。蛋白酶负载的微泡的释放可能是使基质降解甚至在远端位置沉积旁分泌信息的一种机制，从而产生了“最小电阻”的路径，因为肿瘤细胞侵入并通过周围的组织迁移。这与内细胞蛋白水解在Invadopodia上不同，这使局部基质降解并置与前缘。发现可能存在多种蛋白水解侵袭的一种模式，因此限制了任何不包括局灶性和远端蛋白水解的入侵靶向治疗策略的有效性。尽管大量研究已针对细胞侵袭部位的缺乏症形成和功能的理解机制，但微囊泡的生物发生和功能仍然是相对研究的肿瘤生物学领域。然而，最近的证据表明，体液（血液，尿液和腹水）中微泡的真正存在，以及它们作为疾病指标的潜力，扩大了对微丝生物学和功能的兴趣，并加强了研究工作。该应用的总体目标是定义微泡形成的分子机制。该项目的重点是一个中心假设：特定的ARF和RAB蛋白将膜类型蛋白酶和其他蛋白直接到微丝生物发生部位，并且RhoA和Rac1信号之间的紧密互换控制了微伏和Invadopodopodia介导的蛋白质解体蛋白质解体所需的可塑性。我们将解决两个具体目标。在第一个目的中，我们将定义内吞回收途径，该途径将货物引导到微丝菌生物发生部位，并检查特定RAB效应子的募集如何调节基于肌动菌素的基于肌动菌素的收缩。在第二个目标中，我们将检查侵入性肿瘤细胞中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调节的潜在机制，以及RHO信号如何促进该过程。鉴于最近对微囊泡的生物学和临床希望提高了兴趣，这些研究是高度最新的。他们将提高人们对微泡生物发生的了解，并具有为诊断和治疗应用提供靶标的潜力。