Function of the Membrane Type Matrix Metalloproteinase

膜型基质金属蛋白酶的功能

• 批准号: 9008025
• 负责人: STEPHEN J WEISS
• 金额: $ 34.88万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-06-11 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9008025
• 关键词: 3-Dimensional; Behavior Control; Cancer Cell Growth; Carcinoma; Cell Nucleus; Cell Shape; Cell membrane; Cell physiology; Cell surface; Cells; Characteristics; Complex; Cytoskeletal Modeling; Distant; Elements; Environment; Epigenetic Process; Event; Exocytosis; Extracellular Matrix; Extravasation; Gene Targeting; Genetic; Growth; Health; Invaded; Knock-out; Lead; MMP14 gene; MT2-MMP; Malignant Epithelial Cell; Matrix Metalloproteinases; Membrane; Membrane Protein Traffic; Metalloproteases; Molecular; Neoplasm Metastasis; Nuclear; Oncogenic; Outcome; Peptide Hydrolases; Phenotype; Population; Primary Neoplasm; Process; Proliferating; Regulation; Role; Signal Transduction; Site; System; Therapeutic Intervention; Tissues; Transcription Coactivator; Transcriptional Activation; Transcriptional Regulation; cancer cell; cell behavior; cohort; genome-wide analysis; insight; membrane model; membrane-type matrix metalloproteinase; metastatic process; neoplastic cell; novel; programs; response; targeted treatment; trafficking

DESCRIPTION (provided by applicant): The most deadly characteristic of cancer cells is to invade local tissues and establish productive niches outside of the primary tumor site wherein proliferative responses are re-engaged within the specialized confines of the 3-dimensional (3D) extracellular matrix. Current evidence indicates that extravasating cancer cells may reside within distant tissues in a dormant state awaiting further genetic or epigenetic events before initiating proliferative activity. However, the molecular mechanisms that support the re-engagement of proliferative programs in 3D matrix environments remain undefined. Using newly developed conditional knockout models of the membrane-anchored matrix metalloproteinases, MT1-MMP and/or MT2-MMP, we describe new studies demonstrating that these proteolytic enzymes control the post-extravasation, 3D growth of cancer cells by remodeling the surrounding extracellular matrix and activating a YAP/TAZ mechanotransduction axis that controls proliferative responses following the RalA/exocyst-dependent mobilization of the metalloproteinases to the cell surface. Concurrently, MT-MMPs are also unexpectedly routed to the cancer cell nuclear compartment where they also impact proliferation programs by exerting direct transcriptional control of cellular functions. Given these preliminary findings, we outline plans for molecular and cellular studies that seek to i) characterize the role of RalA-exocyst axis regulating MT-MMP trafficking to the cell surface, ii) define the role of the MT- MMP/YAP-TAZ mechanotransduction axis in regulating cancer cell behavior and iii) characterize MT-MMP nuclear trafficking as a novel regulatory hub for controlling cancer cell transcriptional responses These studies should provide new insights into the role of the MT-MMPs in controlling the behavior of cancer cell populations growing within the 3D extracellular matrix and lead to the identification of novel targets for therapeutic intervention.

描述（由申请人提供）：癌细胞最致命的特征是侵入局部组织并在原发性肿瘤部位外建立生产性小生境，其中增殖反应在三维（3D）细胞外基质的专门范围内重新参与。目前的证据表明，外渗的癌细胞可能以休眠状态驻留在远处组织中，等待进一步的遗传或表观遗传事件，然后开始增殖活性。然而，支持在3D矩阵环境中重新参与增殖程序的分子机制仍然不确定。使用新开发的膜锚定基质金属蛋白酶MT 1-MMP和/或MT 2-MMP的条件性敲除模型，我们描述了新的研究，证明这些蛋白水解酶控制渗出后，通过重塑周围的细胞外基质并激活控制RalA/外囊后增殖反应的雅普/TAZ机械转导轴，金属蛋白酶依赖性地动员到细胞表面。同时，MT-MMP也意外地被路由到癌细胞核区室，在那里它们也通过对细胞功能施加直接转录控制来影响增殖程序。鉴于这些初步发现，我们概述了分子和细胞研究的计划，旨在i）表征RalA-外囊轴的作用， 调节MT-MMP向细胞表面的运输，ii）确定MT-MMP/YAP-TAZ机械转导轴在调节癌细胞行为中的作用和iii）表征MT-MMP核运输作为控制癌细胞转录反应的新的调节中心。MMPs在控制癌细胞群体在3D细胞外基质内生长的行为中的作用，并导致用于治疗干预的新靶点的鉴定。