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Professor Sharon Stack
Department of Pathology & Anatomical Sciences
University of Missouri School of Medicine
Columbia, MO 65212 USA
Email: stackm@missouri.edu
Tel: 573 884 7301
Fax: 573 884 8104
Homepage: http://www.stackscientific.com

Research
The ability to invade host tissues and metastasize is the major cause of cancer-related death. During tumor invasion, metastasizing cells attach to the extracellular matrix (ECM), secrete proteinases that degrade ECM proteins, and migrate through the modified basement membrane to establish metastatic foci. Predominant among these proteinases are enzymes in the plasminogen activator (PA) and matrix metalloproteinase (MMP) families. Understanding the molecular mechanisms by which the activity of these metastasis-associated proteinases is regulated is the major focus of my laboratory. Current research centers on three major areas: control of proteinase expression, activation and localization by cell-cell and cell-matrix interactions; protein-protein interactions which regulate enzymatic activity; and alteration of function by limited proteolytic structural modification. Two cancer models are currently in use: ovarian carcinoma and oral squamous cell carcinoma. Studies currently underway include analysis of tumor cell integrin and adhesion profiles, characterization of the effect of specific integrin-mediated cell-matrix and cadherin-mediated cell-cell adhesion events on proteinase regulation, and kinetic analyses of the effect of proteinase:matrix interaction on proteinase activity. Our results suggest that a functional interplay between ECM proteins, tumor cells, and proteolytic enzymes may serve as a fine regulatory mechanism for highly localized control of pericellular proteolytic activity in the tumor cell microenvironment.
Collaborations
Maria Barbolina, University of Illinois, Chicago, IL
Peter Friedl, Nijmegen, Holland
Laurie Hudson, University of New Mexico, Albuquerque, NM
HG Munshi, Northwestern University, Chicago, IL
Katarina Wolf, Holland
Publications
Ghosh, S., Johnson J.J., Sen, R., Mukhopadhyay S., Liu, Y., Zhang, F., Wei, Y., Chapman, H.A., and Stack, M.S. (2006) Functional Relevance of Urinary-type Plasminogen Activator Receptor (uPAR)-alpha3beta1 Integrin Association in Proteinase Regulatory Pathways. J. Biol. Chem.281:13021-9.
Munshi, H.G. and Stack, M.S. (2006) Reciprocal Interactions Between Adhesion Receptor Signaling and MMP Regulation, for Cancer Metastasis Reviews 25: 45-56.
Barbolina, M.V., Ariztia, E.V., Adley, B.P., Liu, Y., and Stack, M.S. (2007) Microenvironmental Regulation of Membrane Type 1 Matrix Metalloproteinase (MT1-MMP) Activity in Ovarian Carcinoma Cells via Collagen-Induced Egr-1 Expression. J. Biol. Chem. 282:4924-31.
Symowicz, J.E., Adley, B.P., Gleason, K., Fishman, D.A., Hudson, L.G. and Stack, M.S. (2007) Integrin Engagement Promotes Proteinase-Dependent E-Cadherin Ectodomain Shedding in Ovarian Carcinoma Cells. Cancer Research 67: 2030-9.
Wolf, K., Wu, Y.I., Liu, Y., Tam, E., Geiger J., Brocker E.B., Overall C., Stack M. S. and Friedl P. (2007) High resolution topography and outcome of pericellular proteolysis: belt-cleavage, path generation and invasive tumor cell patterning . Nature Cell Biology 9:893-904.
Shi, Z., and Stack, M.S. (2007) Urinary-Type Plasminogen Activator (uPA) and its Receptor (uPAR) in Oral Squamous Cell Carcinoma of the Oral Cavity. Biochemical Journal 407: 153-9.
Barbolina, M. and Stack, M.S. (2008) Membrane Type-1 Matrix Metalloproteinase: Substrate Diversity in Pericellular Proteolysis. W. Parks, Ed. Seminars in Cell and Develop. Biol., 19:24-33.
Pettus, J., Johnson, J.J., Shi, Z., Davis, J.W., Koblinski, J.K., Ghosh, S., Liu, Y., Ravosa, M.J., Frazier, S. and Stack, M.S. (2008) Multiple Kallikrein (5, 7, 8, and 10) Expression in Squamous Cell Carcinoma of the Oral Cavity. Histology & Histopathology 24:197-207.
Moss, N.M., Liu, Y., Johnson, J.J., Debiase P., Jones J., Hudson, L.G., Munshi H.G., and Stack, M.S. (2009) Epidermal Growth Factor Receptor-Mediated Membrane Type 1 Matrix Metalloproteinase Endocytosis Regulates the Transition Between Invasive and Expansive Growth in Three-Dimensional Collagen. Molecular Cancer Research, in press.
Moss N.M., Barbolina M.V., Liu Y., Sun L., Munshi H.G., and Stack, M.S. (2009) Ovarian Carcinoma Cell Detachment and Multi-cellular Aggregate Formation are Regulated by MT1-MMP: A Potential Role in Intra-Peritoneal Metastatic Dissemination. Cancer Research, in press.





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