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：
8462943
负责人：
Christopher E Turner
金额：
$ 31.11万
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/8462943
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

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（由适用提供）：癌细胞从原发性肿瘤质量及其随后转移到远处器官的迁移被认为是癌症进展的致命步骤，并且与大多数癌症死亡率有关。此外，单个癌细胞似乎能够通过在运动症和变形虫模式之间切换到运动性模式之间，从而避免当前的入侵和转移药物干预。控制这种表型可塑性的细胞机制知之甚少。最近，我们在调节肿瘤细胞可变，侵袭和转移的调节中鉴定了密切相关的粘合剂相关支架蛋白质蛋白和HIC-5的不同功能。在该建议中，使用已建立的癌细胞系以及从原发性肿瘤中分离出来的细胞，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-触觉细胞基质中，在体外模型系统中。小鼠的异种移植研究将用于评估帕西林和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帕克西林和HIC-5的相对作用，控制肿瘤细胞侵袭的模式，并识别相关的功能域和信号传导途径。我们将使用类似的方法来研究帕西林在调节基质金属蛋白酶-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。 HIC-5在TGF-诱导的上皮间质转变期间进行更新。还将检查HIC-5在TGF-依赖性细胞侵袭中通过基质降解的Invadopodia的形成和功能的作用。拟议的研究将提供有关控制肿瘤细胞迁移和侵袭以及其表型可塑性协调的潜在细胞机制的洞察力，将来可能会提出用于检测或治疗转移性癌症的新型策略。