Function of Membrane Type Matrix Metalloproteinase

摘要 癌细胞最致命的特征是它们侵入局部组织和转移的能力。 目前的证据表明，癌细胞的增殖，侵袭和转移能力是 以癌细胞自主的方式以及由周围的细胞和非细胞的方式调节 微环境使用MT 1-MMP条件性敲除小鼠，与人类患者- 我们最近报道，癌细胞来源的MT 1-MMP在肿瘤细胞中起着重要的作用。 在驱动局部组织侵袭和转移中起主导作用。然而，我们意外地发现， 单独靶向癌细胞MT 1-MMP在体内引发转录水平的大规模变化， 癌细胞的程序远远超出了细胞-细胞外基质（ECM）的调节 交互.这些结果表明，MT 1-MMP发挥更全面的影响，癌细胞的功能 比以前欣赏。我们为MT 1-MMP调控癌细胞的发生提供了新的证据， 通过调节一种新的机械转导级联来表达基因， 核纤层蛋白A/C水平，伴随着对共转录激活因子雅普和TAZ的影响， MRTF-SRF转录网络。此外，初步研究表明，MT 1-MMP发挥作用， 这些作用以蛋白酶依赖的方式通过影响富含I型胶原的， 间质ECM。最后，在监测MT 1-MMP向侵袭足结构的运输的同时， ECM重塑，我们已经发现了一个迄今未描述的过程，其中MT 1-MMP易位 从早幼粒细胞白血病蛋白（PML）丰富的核内陷到ECM降解位点， 与细胞质RNA结合蛋白UNR/CSDE 1相关的细胞表面。鉴于这些发现， 我们概述了分子和细胞研究相结合的计划，这些研究试图i）将MT 1-MMP定义为一种 机械转导相关癌细胞转录程序的主要上游调节因子 ii）将MT 1-MMP/I型胶原轴的作用表征为侵袭和转移所必需的， 负责控制体内癌细胞行为的关键决定因素，和iii）确定 新的核出芽启动的MT 1-MMP-PML/UNR相互作用网络在控制蛋白酶中的作用 递送至基质降解侵袭体。总之，这些研究试图将MT 1-MMP鉴定为 在体内肿瘤进展的主要蛋白水解效应子，凭借其控制肿瘤细胞行为的能力， 在原发性和继发性肿瘤中遇到的嵌入I型胶原丰富的3D ECM内的癌细胞群， 体内转移部位。

Abstract The most deadly characteristic of cancer cells is their ability to invade local tissues and metastasize. Current evidence suggests that carcinoma cell proliferative, invasive and metastatic potential are regulated in a cancer cell-autonomous fashion as well as by the surrounding cellular and acellular microenvironment. Using MT1-MMP conditional knockout mice, in combination with human patient- derived cancer xenografts, we have recently reported that carcinoma cell-derived MT1-MMP plays a dominant role in driving local tissue invasion and metastasis. Unexpectedly, however, we find that targeting carcinoma cell MT1-MMP alone in vivo triggers large scale changes in the transcriptional program of the cancer cells that extend far beyond the regulation of cell-extracellular matrix (ECM) interactions. These results suggest that MT1-MMP exerts a more global effect on carcinoma cell function than previously appreciated. Indeed, we provide new evidence that MT1-MMP controls carcinoma cell gene expression by regulating a novel mechanotransduction cascade that centers on the regulation of nuclear lamin A/C level with attendant effects on the co-transcriptional activators, YAP and TAZ and the MRTF-SRF transcriptional network. Furthermore, preliminary studies indicate that MT1-MMP exerts these effects in a proteinase-dependent fashion by effecting the remodeling of the type I collagen-rich, interstitial ECM. Finally, while monitoring the trafficking of MT1-MMP to invadopodial structures during ECM remodeling, we have uncovered a heretofore undescribed process wherein MT1-MMP translocates from promyelocytic leukemia protein (PML)-rich nuclear invaginations to ECM-degradative sites at the cell surface in association with the cytoplasmic RNA-binding protein, UNR/CSDE1. Given these findings, we outline plans for a combination of molecular and cellular studies that seek to i) define MT1-MMP as a master upstream regulator of the mechanotransduction-linked carcinoma cell transcription programs required for invasion and metastasis, ii) characterize the role of the MT1-MMP/type I collagen axis as the key determinant responsible for controlling carcinoma cell behavior in vivo and iii) establish the role of a novel, nuclear budding-initiated, MT1-MMP-PML/UNR interaction network in controlling proteinase delivery to matrix-degradative invadosomes. Together, these studies seek to identify MT1-MMP as the dominant proteolytic effector of tumor progression in vivo by virtue of its ability to control the behavior of cancer cell populations embedded within the type I collagen-rich 3D ECM encountered at primary and metastatic sites in vivo.