Function of the Membrane Type Matrix Metalloproteinase

描述(申请人提供)：癌细胞最致命的特征是侵袭局部组织，并在原发肿瘤部位之外建立生产性的壁龛，其中增殖反应在三维(3D)细胞外基质的专门范围内重新进行。目前的证据表明，渗出的癌细胞可能以休眠状态存在于远处组织中，等待进一步的遗传或表观遗传事件，然后才开始增殖活动。然而，支持3D基质环境中增殖程序重新参与的分子机制仍不清楚。利用新开发的膜锚定基质金属蛋白酶的条件性敲除模型，MT1-MMPs和/或MT2-MMPs，我们描述了新的研究表明，这些蛋白水解酶通过重塑周围的细胞外基质和激活YAP/TAZ机械转导轴来控制癌细胞的后外渗和3D生长，YAP/TAZ机械转导轴控制依赖于Rala/外囊的金属蛋白酶动员到细胞表面后的增殖反应。同时，MT-MMPs也出人意料地被送到癌细胞的核间室，在那里它们也通过对细胞功能的直接转录控制来影响增殖计划。根据这些初步发现，我们概述了分子和细胞研究的计划，这些研究试图：1)表征Rala-外囊轴的作用 第二，确定MT-MMP/YAP-TAZ机械转导轴在调控癌细胞行为中的作用；iii)将MT-MMP核转运表征为控制癌细胞转录反应的新的调控枢纽。这些研究将为MT-MMPs在控制3D细胞外基质内生长的癌细胞群体的行为中所扮演的角色提供新的见解，并导致确定治疗干预的新靶点。

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.