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

Paxillin 和 Hic-5 协调癌细胞侵袭机制

基本信息

批准号：
8627588
负责人：
Christopher E Turner
金额：
$ 32.1万
依托单位：
UPSTATE MEDICAL UNIVERSITY
依托单位国家：
美国
项目类别：
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/8627588
关键词：
Adaptor Signaling Protein Adhesions Biochemical Biological Assay Biological Models Breast Epithelial Cells Cancer cell line Cardiovascular system Cells Cellular Morphology Characteristics Clathrin Complex Cytoskeleton Data Detection Developmental Process Disseminated Malignant Neoplasm Distant Endocytosis Epithelial 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 MCF10A cells MDA MB 231 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

项目摘要

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.

描述（由申请人提供）：癌细胞从原发肿瘤块迁移并随后转移到远处器官被认为是癌症进展中的致命步骤，并且与大多数癌症死亡相关。此外，个体癌细胞出现能够通过在间充质和变形虫运动模式之间切换来逃避当前的侵袭和转移的药物干预。我们最近对控制这种表型可塑性的细胞机制知之甚少。相关的粘附相关支架蛋白桩蛋白和 Hic-5 在肿瘤细胞可塑性、侵袭和转移的调节中的作用在本提案中，我们将使用已建立的癌细胞系以及从原发性肿瘤中分离的细胞来应用最新技术。在小鼠体内的 3D 细胞外基质异种移植研究中，将使用艺术实时成像技术来跟踪肿瘤细胞形态和迁移以及粘附和细胞骨架动力学，以评估桩蛋白的相对影响。我们将利用 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各自的作用，并确定相关的功能域和信号通路。我们将使用类似的方法来研究桩蛋白在基质金属蛋白酶-2 (MMP-2) 运输和分泌的调节中的作用，以控制间充质肿瘤侵袭策略的上调。转化生长因子-¿ -诱导上皮间质转化 Hic-5 在 TGF-¿还将通过基质降解侵袭伪足的形成和功能来检查依赖性细胞侵袭，所提出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，并且可能在未来进行。提出检测或治疗转移性癌症的新策略。