Paxillin and Hic-5 in Coordination of Cancer Cell Invasion Mechanisms

Paxillin 和 Hic-5 协调癌细胞侵袭机制

• 批准号: 8216208
• 负责人: Christopher E Turner
• 金额: $ 33.1万
• 依托单位: UPSTATE MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8216208
• 关键词: Adaptor Signaling Protein; Adhesions; Biochemical; Biological Assay; Biological Models; Breast; Cancer cell line; Cardiovascular system; Cells; Cellular Morphology; Characteristics; Clathrin; Complex; Cytoskeleton; Data; Detection; Developmental Process; Disseminated Malignant Neoplasm; Distant; Endocytosis; Epithelial; Epithelial Cells; Equilibrium; Exocytosis; Extracellular Matrix; Family; Focal Adhesions; Future; Gel; Gelatin; Gelatinase A; Guanosine Triphosphate Phosphohydrolases; Imaging Techniques; Immunofluorescence Microscopy; In Situ; In Vitro; Individual; Intervention; Malignant Neoplasms; Mammary Neoplasms; Matrix Metalloproteinases; Mediating; Mesenchymal; Mesenchymal Cell Neoplasm; Modeling; Molecular Analysis; Monitor; Morphology; Mus; Neoplasm Metastasis; Organ; Pathway interactions; Patients; Phenotype; Population; Positioning Attribute; Primary Neoplasm; Prognostic Factor; Protein Overexpression; Proteins; RNA Interference; Recycling; Regulation; Relative (related person); Reporter; Research; Role; Scaffolding Protein; Secondary to; Signal Pathway; Signal Transduction; Site; Surveys; System; Testing; Therapeutic; Time; Tumor Cell Invasion; Tumor Cell Line; Up-Regulation; Vesicle; Xenograft procedure; cancer cell; cell motility; clinically relevant; fluorescence imaging; in vitro Model; in vivo; inhibitor/antagonist; insight; migration; mortality; mutant; neoplastic cell; novel; novel strategies; overexpression; paxillin; protein expression; rho; trafficking; tumor; tumor progression

DESCRIPTION (provided by applicant): The migration of cancer cells away from the primary tumor mass and their subsequent metastasis to distant organs is regarded as a fatal step in cancer progression and is associated with the majority of cancer mortalities. Furthermore, individual cancer cells appear to be able to evade current pharmacologic intervention of invasion and metastasis by switching between mesenchymal and amoeboid modes of motility. The cellular mechanisms controlling this phenotypic plasticity are poorly understood. We have recently identified distinct functions for the closely related adhesion-associated scaffold proteins paxillin and Hic-5 in the regulation of tumor cell plasticity, invasion and metastasis. In this proposal, using established cancer cell lines, as well as cells isolated from primary tumors, we will apply state-of-the art real-time imaging techniques to track tumor cell morphology and migration as well as adhesion and cytoskeletal dynamics in 3D-extracellular matrix in vitro model systems. Xenograft studies in mice will be used to evaluate the relative impact of paxillin and Hic-5 signaling on tumor progression and metastasis in vivo. We will use RNA interference and mutant protein expression to dissect the respective roles for paxillin and Hic-5 in controlling the mode of tumor cell invasion and identify the pertinent functional domains and signaling pathways. We will use similar approaches to study a role for paxillin in the regulation of matrix metalloproteinase-2 (MMP-2) trafficking and secretion to control mesenchymal tumor invasion strategies. Hic-5 is upregulated during TGF-¿-induced epithelial mesenchymal transition. The role of Hic-5 in TGF-¿-dependent cell invasion, through the formation and function of matrix-degrading invadopodia, will also be examined. The proposed studies will provide insight into the underlying cellular mechanisms controlling tumor cell migration and invasion and the coordination of their phenotypic plasticity and may in the future suggest novel strategies for detection or treatment of metastatic cancers. PUBLIC HEALTH RELEVANCE: Tumor cell invasion and metastasis to secondary sites is the single worst prognostic factor dictating patient long-term survival. The ability of tumor cells to switch between distinct modes of migration, called plasticity, is an important factor in the limited efficacy of invasion-directed therapeutics. The signaling mechanisms mediating cancer cell plasticity remain poorly understood. The proposed research will describe new roles for two closely related adhesion associated adaptor proteins, paxillin and Hic-5, in the regulation of cancer cell migration, plasticity and matrix-metalloproteinase function and thereby increase our understanding of cancer progression, malignancy and metastasis.

描述（由申请人提供）：癌细胞从原发性肿瘤块迁移并随后转移至远处器官被认为是癌症进展中的致命步骤，与大多数癌症死亡相关。 此外，个别癌细胞似乎能够逃避目前的药物干预的侵袭和转移之间的切换间充质和变形虫的运动模式。 控制这种表型可塑性的细胞机制知之甚少。 最近，我们已经确定了密切相关的粘附相关的支架蛋白桩蛋白和Hic-5在调节肿瘤细胞的可塑性，侵袭和转移的不同功能。 在这项提案中，使用已建立的癌细胞系，以及从原发性肿瘤中分离的细胞，我们将应用最先进的实时成像技术来跟踪肿瘤细胞的形态和迁移，以及在3D细胞外基质体外模型系统中的粘附和细胞骨架动力学。 小鼠异种移植研究将用于评估桩蛋白和Hic-5信号传导对体内肿瘤进展和转移的相对影响。 我们将使用RNA干扰和突变蛋白表达来剖析桩蛋白和Hic-5在控制肿瘤细胞侵袭模式中的各自作用，并确定相关的功能结构域和信号通路。 我们将使用类似的方法来研究桩蛋白在调节基质金属蛋白酶-2（MMP-2）的运输和分泌以控制间充质肿瘤侵袭策略中的作用。 Hic-5在TGF-β诱导的上皮间质转化过程中上调。 Hic-5在TGF-β依赖性细胞侵袭中的作用，通过基质降解侵袭伪足的形成和功能，也将被检查。 拟议的研究将深入了解控制肿瘤细胞迁移和侵袭的潜在细胞机制及其表型可塑性的协调，并可能在未来提出检测或治疗转移性癌症的新策略。 公共卫生关系：肿瘤细胞浸润和转移到继发部位是决定患者长期生存的唯一最差预后因素。 肿瘤细胞在不同的迁移模式之间切换的能力，称为可塑性，是侵袭导向疗法疗效有限的一个重要因素。 介导癌细胞可塑性的信号传导机制仍然知之甚少。 这项研究将描述两种密切相关的粘附相关衔接蛋白，桩蛋白和Hic-5，在调节癌细胞迁移，可塑性和基质金属蛋白酶功能中的新作用，从而增加我们对癌症进展，恶性和转移的理解。