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Function of Membrane Type Matrix Metalloproteinase

膜型基质金属蛋白酶的功能

基本信息

批准号：
9896984
负责人：
STEPHEN J WEISS
金额：
$ 37.05万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-06-11 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9896984
关键词：
3-Dimensional Anabolism Automobile Driving Behavior Control Breast Cancer Patient Cancer Control Carcinoma Cell Proliferation Cell physiology Cell surface Characteristics Collagen Type I Complex Deposition Elements Event Extracellular Matrix Follow-Up Studies Gene Expression Genetic Transcription Human In Vitro Invaded Knock-in Mouse Knockout Mice Laboratories Lamin Type A Link MMP14 gene MT2-MMP Malignant Epithelial Cell Malignant Neoplasms Matrix Metalloproteinases Membrane Messenger RNA Modeling Molecular Monitor Neoplasm Metastasis Nuclear Nuclear Lamin Nuclear Protein Outcome Pathway interactions Patients Peptide Hydrolases Play Population Process Publishing RNA-Binding Proteins Regulation Reporting Reticulum Role Series Site Structure Therapeutic Intervention Tissues Traction Transcription Coactivator Xenograft procedure cancer cell cell behavior cell stroma conditional knockout crosslink density extracellular in vivo insight interstitial malignant breast neoplasm mechanical properties mechanotransduction membrane-type matrix metalloproteinase mouse model neoplastic cell novel programs targeted treatment trafficking transcription factor PML transcriptome tumor progression

项目摘要

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.

摘要