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Cytoskeletal Dynamics in Pancreatic Cancer Metastasis

胰腺癌转移中的细胞骨架动力学

基本信息

批准号：
9315108
负责人：
MARK A. MC NIVEN
金额：
$ 29.94万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-08-01 至 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9315108
关键词：
3-Dimensional Actins Adenocarcinoma Cell Adhesions Affect American Arts Attenuated Binding Binding Proteins Biological Models Cell Adhesion Cell membrane Cell model Cells Complex Cytoskeletal Proteins Disease Dynamin 2 Elements Environment Event Exhibits Experimental Models Fibroblasts Funding Genetic Glean Guanine Nucleotide Exchange Factors Guanosine Triphosphate Phosphohydrolases Human In Situ Invaded Libraries Link MMP2 gene Malignant Neoplasms Malignant neoplasm of pancreas Maps Metalloproteases Metastatic to Modeling Molecular Monomeric GTP-Binding Proteins Mutation Neoplasm Metastasis Network-based Oncogenes Oncogenic Organ Pancreas Pancreatic Ductal Adenocarcinoma Pathway interactions Patients Peptide Hydrolases Peripheral Pharmacology Play Polymers Population Process Proteins Publishing Recruitment Activity Regulation Resected Role Series Signal Transduction Stromal Cells Stromal Invasion Stromal Neoplasm Structure Testing Therapeutic Transactivation Tumor Cell Invasion actin 2 alpha Actinin base cancer cell cell motility defined contribution design differential expression imaging modality inhibitor/antagonist insight killings knock-down live cell imaging metastatic process migration mouse model neoplastic cell novel novel therapeutics pancreatic cancer cells pancreatic neoplasm paracrine public health relevance scaffold stellate cell tool tumor

项目摘要

DESCRIPTION (provided by applicant): Pancreatic cancers are particularly lethal and known for aggressive metastatic invasion. Over the prior funding period we have gathered substantial published and unpublished observations providing insight into how cells from these tumors disseminate. These findings support our CENTRAL HYPOTHESIS predicting that invasive pancreatic tumor cells and associated stromal cells in situ form a dynamic actin-based "invadosome" at the leading edge that selectively recruits specific metalloproteases to support adhesion, migration, and matrix remodeling during metastatic invasion. This hypothesis will test the contributions of the large polymeric GTPase Dynamin2 that forms a contractile scaffold linking the invadosome actin-based network to the advancing cell membrane. We will pursue three related but distinct specific aims that will provide mechanistic insights into the machinery, signaling, and degradative process utilized by invading PDAC cells and associated stroma. These aims include: One, defining the Dyn2/actin-based machinery that is essential for "invadosome" extension during migration in a 3-dimensional environment and in situ, with special emphasis on the expression, interaction, and function of the oncogenic actin adaptors, a-actinin 1 and 4, Two, understanding the regulation of invadosome dynamics by small oncogenic GTPases, that directly bind Dyn2, with an emphasis on a therapeutic approach, and Three, defining the mechanisms of matrix remodeling by the Dyn2- centric invadosome through the identification of novel pathways that regulate protease activity. This proposal will apply stat-of-the-art live-cell imaging methods to multiple experimental model systems that manipulate mixed populations of tumor and stromal cells in a 3D environment, as well as tumors resected from genetic mouse models and from human PDAC patients. The information gleaned from these approaches will greatly expand our mechanistic understanding of this disease while developing new therapies and treatments.

描述(申请人提供)：胰腺癌特别致命，以侵袭性转移而闻名。在之前的资助期间，我们收集了大量已发表和未发表的观察结果，为这些肿瘤的细胞如何扩散提供了洞察力。这些发现支持我们的中心假设，即侵袭性胰腺肿瘤细胞和相关的间质细胞在原位形成一个动态的基于肌动蛋白的“侵袭体”，它选择性地招募特定的金属蛋白来支持转移侵袭过程中的黏附、迁移和基质重塑。这一假说将检验大的聚合GTP酶Dynamin2的作用，该酶形成一个收缩的支架，将基于肌动蛋白的侵袭体网络连接到前进的细胞膜。我们将追求三个相互关联但截然不同的具体目标，以提供对机器的机械性见解，信号，以及入侵的PDAC细胞和相关间质所利用的降解过程。这些目标包括：一，确定在三维环境和原位迁移过程中，“侵略体”延伸所必需的基于dy2/肌动蛋白的机制，特别强调致癌肌动蛋白适配器α-肌动蛋白1和4的表达、相互作用和功能；二，了解小致癌GTP酶对侵袭体动力学的调节，强调一种治疗方法；三，通过识别调节蛋白酶活性的新途径，定义以dy2为中心的侵袭体的基质重塑的机制。这项提议将把最先进的活细胞成像方法应用于多个实验模型系统，这些系统在3D环境中操纵肿瘤和基质细胞的混合种群，以及从遗传小鼠模型和人类PDAC患者中切除的肿瘤。从这些方法中收集的信息将极大地扩展我们对这种疾病的机械理解，同时开发新的治疗方法和治疗方法。