Normal as well as neoplastic cells invade surrounding tissues by mobilizing proteolytic enzymes that allow them to degrade the structural barriers established by the extracellular matrix. One group of proteinases, known as the matrix-degrading metalloproteinases or MMPs, is currently believed to play a prominent role in matrix remodeling events since these enzymes can, in concert, degrade all of the major proteinaceous components of the extracellular matrix including collagens, elastin and proteoglycans. Recently, the first membrane-anchored member of the MMP family, termed the membrane type-1 MMP (MT1-MMP), was identified and shown to be expressed not only in normal mesenchymal/epithelial cell types, but also at heightened levels in a variety of human carcinomas. Based on the ability of MT1-MMP to activate progelatinase A and/or collagenase-3, it has been postulated that this metalloproteinase axis may act as the "master switch" that regulates the expression of the tissue-invasive phenotype. However, increasing evidence suggests that MT1-MMP plays a direct and critical - role in regulating cell-matrix interactions. More recent data now indicate that MT1-MMP activity may be complemented by a second, membrane-anchored MMP, termed MT2-MMP. While little is known with regard to MT2-MMP structure or function, the protease is postulated to play a dominant, and heretofore, unsuspected role in regulating normal and neoplastic epithelial cell function. To this end, we seek to use a series of molecular, genetic and cellular approaches to i) characterize MT2-MMP structure and function relationships in extracellular matrix degradation and invasion, ii) define the relative roles of MT2-MMP and MT1-MMP in normal tissue development and iii) characterize the functional impact of MT2-MMP and/or MT1-MMP on cancer growth, invasion and metastasis in vivo. These studies should provide new insights into the role of the MT-MMPs in normal as well as neoplastic cell populations and define their potential importance as targets for novel therapeutic interventions.

Public Health Relevance

These studies should provide new insights into the role of the MT-MMPs in normal and neoplastic cell populations and define their potential importance as targets for novel therapeutic interventions.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA071699-15
Application #
8271318
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Woodhouse, Elizabeth
Project Start
1997-06-11
Project End
2013-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
15
Fiscal Year
2012
Total Cost
$305,059
Indirect Cost
$98,715
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Tang, Yi; Rowe, R Grant; Botvinick, Elliot L et al. (2013) MT1-MMP-dependent control of skeletal stem cell commitment via a ?1-integrin/YAP/TAZ signaling axis. Dev Cell 25:402-16
Wolf, Katarina; Te Lindert, Mariska; Krause, Marina et al. (2013) Physical limits of cell migration: control by ECM space and nuclear deformation and tuning by proteolysis and traction force. J Cell Biol 201:1069-84
Willis, A L; Sabeh, F; Li, X-Y et al. (2013) Extracellular matrix determinants and the regulation of cancer cell invasion stratagems. J Microsc 251:250-60
Shimizu-Hirota, Ryoko; Xiong, Wanfen; Baxter, B Timothy et al. (2012) MT1-MMP regulates the PI3K?·Mi-2/NuRD-dependent control of macrophage immune function. Genes Dev 26:395-413
Koenig, Gerald C; Rowe, R Grant; Day, Sharlene M et al. (2012) MT1-MMP-dependent remodeling of cardiac extracellular matrix structure and function following myocardial infarction. Am J Pathol 180:1863-78
Rowe, R Grant; Keena, Daniel; Sabeh, Farideh et al. (2011) Pulmonary fibroblasts mobilize the membrane-tethered matrix metalloprotease, MT1-MMP, to destructively remodel and invade interstitial type I collagen barriers. Am J Physiol Lung Cell Mol Physiol 301:L683-92
Lu, Changlian; Li, Xiao-Yan; Hu, Yuexian et al. (2010) MT1-MMP controls human mesenchymal stem cell trafficking and differentiation. Blood 115:221-9
Chun, Tae-Hwa; Inoue, Mayumi; Morisaki, Hiroko et al. (2010) Genetic link between obesity and MMP14-dependent adipogenic collagen turnover. Diabetes 59:2484-94
Sabeh, Farideh; Li, Xiao-Yan; Saunders, Thomas L et al. (2009) Secreted versus membrane-anchored collagenases: relative roles in fibroblast-dependent collagenolysis and invasion. J Biol Chem 284:23001-11
Ota, Ichiro; Li, Xiao-Yan; Hu, Yuexian et al. (2009) Induction of a MT1-MMP and MT2-MMP-dependent basement membrane transmigration program in cancer cells by Snail1. Proc Natl Acad Sci U S A 106:20318-23

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