Molecular Mechanisms of Cell Invasion

细胞侵袭的分子机制

• 批准号: 8511580
• 负责人: CRISLYN D'SOUZA-SCHOREY
• 金额: $ 26.33万
• 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/8511580
• 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）：这是一份研究浸润性肿瘤细胞中微泡生物发生机制的申请。它建立在先前NIH资助的一种独特的囊泡群的令人兴奋的发现之上，这种囊泡被称为微囊泡，它含有功能活跃的蛋白酶，当肿瘤细胞获得侵袭潜力时被释放出来。承载蛋白酶的微泡的释放可能是导致基质降解的一种机制，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周围组织时创造“最小阻力”的路径。这是不同的细胞外蛋白水解在invadopdia，使局部基质降解并置前缘。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灶性和远端蛋白水解的靶向侵袭治疗策略的有效性。虽然大量的研究都是为了了解细胞侵袭部位的侵入性囊泡形成和功能的机制，但微泡的生物发生和功能仍然是肿瘤生物学中一个相对缺乏研究的领域。然而，最近越来越多的证据表明，体液（血液、尿液和腹水）中确实存在微囊泡，它们有可能作为疾病的指标，这扩大了人们对微囊泡生物学和功能的兴趣，并加强了研究工作。本应用程序的首要目标是定义微泡形成的分子机制。该项目的核心假设是，特定的ARF和Rab蛋白将膜型蛋白酶和其他蛋白质直接引导到微泡生物发生的位点，RhoA和Rac1信号之间的紧密交换控制了微泡和侵入物介导的蛋白水解入侵之间切换所需的可塑性。我们将讨论两个具体目标。在第一个目标中，我们将定义将货物引导到微泡生物发生位点的内噬循环途径，并研究特定Rab效应物的招募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，我们将研究侵袭性肿瘤细胞中RhoA和Rac1的空间激活。我们还将研究在微泡形成过程中调控Rac1下调的潜在机制，以及Rho信号如何促进这一过程。鉴于最近对微囊泡的生物学和临床前景的高度兴趣，这些研究是高度流行的。他们将推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。