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Bonnie F. Sloane, Ph.D.
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RESEARCH INTERESTS:
Dr. Sloane’s laboratory has a longstanding interest is in the roles of proteases in development and progression of cancer, with an emphasis on breast, colon and prostate cancers. Her research group has established a role for lysosomal proteases, primarily the cysteine protease cathepsin B, and the endogenous inhibitors of cysteine cathepsins (the cystatins and stefins) in malignant progression. They were the first group to uncover molecular mechanisms for the increased expression of cathepsin B in human tumors and to identify binding partners responsible for alterations in localization of cathepsin B in tumors. This includes the association of cathepsin B with caveolae on the cell surface via the direct binding of procathepsin B to S100A10, p11 or the light chain of the annexin II heterotetramer, in complex with the heavy chain annexin II.
The Sloane group has been a leader in the implementation of cellular imaging in the protease field. They established new assays to follow proteolysis by live cells over time as they form three dimensional structures in matrices and migrate through the matrices, thus analyzing proteolysis in four dimensions. They have employed these assays to follow the interactions among tumor cells and tumor and tumor-associated cells in an effort to determine whether the various cellular components comprising a tumor use proteolysis to perform their functions (e.g., is there proteolysis associated with infiltration of macrophages into tumors? With endothelial cell migration and formation of neovessels?) and the contributions of the individual cellular components to collective tumor proteolysis. Using such techniques, they have demonstrated that the interactions of stromal fibroblasts and inflammatory macrophages with breast and colon tumor cells increase proteolysis of extracellular matrix proteins. Furthermore, their studies have revealed that no single protease or class of proteases is responsible for degradation of collagen, but rather that interactions among three classes of proteases (cysteine, serine and matrix metalloproteinases) are responsible. In addition, because the Sloane group is studying proteolysis by live cells they have been able to demonstrate that there is an intracellular proteolytic component to collagen degradation that employs lysosomal cysteine cathepsins. Recent work by one of the collaborators on Dr. Sloane’s DOD Breast Cancer of Excellence, i.e., Dr. Thomas Bugge (NIDCR), identified a cell surface protein, uPARAP, that mediates the uptake of the collagens into the lysosomes and further showed that growth of mammary tumors in mice is reduced if uPARAP is genetically ablated. Intriguingly, uPARAP is not expressed by the tumor cells themselves, but by the fibroblasts associated with the mammary tumors. This collaborative work thus substantiates a critical role for the tumor microenvironment in tumor growth, in this case a critical role for interactions between tumor and host cells.
Ongoing collaborative studies with Dr. Mattingly and the Center on Proteolytic Pathways (CPP), an NIH Roadmap National Technology Center for Networks and Pathways, are directed toward defining proteolytic pathways and their intersections with kinase pathways in tumors and the tumor microenvironment. Their intent is to delineate mechanisms by which the tumor microenvironment impacts proteolysis with an eye toward developing therapeutic strategies to target interactions between the tumor and its microenvironment. With the CPP, and in collaboration with Drs. Auner, Duric, Hoffman and Meade, the methodologies and probes used to image protease activity in vitro are being modified for use in vivo, preferably for non-invasive imaging. Their ultimate goal is to develop methods and probes to monitor the efficacy of drugs targeting proteases as well as the ability of those drugs to reach and inhibit target proteases in vivo, thus providing a surrogate endpoint for clinical trials directed against proteolytic pathways in the tumor microenvironment.
Current Lab Personnel- Faculty
- Dora Cavallo-Medved, Ph.D. (Research Assistant Professor)
- Kamiar Moin, Ph.D. (Associate Professor)
- Izabela Podgorski, Ph.D. (Research Assistant Professor)
- Graduate Students
- Christopher Jedeszko (Ph.D. candidate in Pharmacology; DOD Breast Cancer Predoctoral Trainee)
- Bernadette Victor (Ph.D. candidate in Cancer Biology; DOD Breast Cancer Predoctoral Trainee)
- Research Associate
- Mansoureh Sameni (Research Associate)
- Research Assistants
- Anita Chalasani
- Julie Dosescu
- Deborah Rudy
Some Lab Alumni
- Mamoun Ahram, Ph.D. (Ph.D. in Cancer Biology 1999), Assistant Dean for Testing Affairs and College Development, Faculty of Medicine, Mutah University, Mutah, Jordan.
- Isabelle Berquin, Ph.D. (Ph.D. in Cancer Biology 1995), Assistant Professor of Pathology, Wake Forest University, Winston-Salem, NC
- Michael Emmert-Buck, M.D.-Ph.D. (Ph.D. in Pharmacology 1989), Head, Pathogenetics Unit, Laboratory of Pathology, Advanced Technology Center, National Cancer Institute/NIH, Gaithersburg, MD
- Jennifer Koblinski, Ph.D. (Ph.D. in Cancer Biology 1999), Research Assistant Professor of Pathology, Northwestern University, Chicago, IL
- Tamara Turnsek Lah, Ph.D. (Postdoc 1985-87), Director, National Institute of Biology, Ljubljana, Slovenia
- Mona Mostafa Mohamed, Ph.D. (Avon/American Association for Cancer Research International Fellow 2005-07), Associate Professor of Biological Sciences, Cairo University, Cairo, Egypt
Current Collaborators
- Greg Auner, Ph.D., Smart Sensors and Integrated Microsystems Program and Neb Duric, Ph.D., Karmanos Cancer Institute, Wayne State University, Detroit, MI
- Matthew Bogyo, Ph.D., Stanford University, Stanford, CA
- Lisa Coussens, Ph.D., University of California at San Francisco, CA
- Edith Elliott, Ph.D., University of KwaZulu-Natal, Pietermaritzburg, South Africa
- Robert Gillies, Ph.D., Moffitt Cancer Center, Tampa, FL
- James Granneman, Center for Integrative Metabolic and Endocrine Research and Department of Psychiatry, Wayne State University, Detroit, MI
- Brian Hoffman, Ph.D. and Thomas Meade, Ph.D., Northwestern University, Evanston, IL
- Lynn Matrisian, Ph.D., Vanderbilt University, Nashville, TN
- Raymond Mattingly, Ph.D., Department of Pharmacology, Wayne State University, Detroit, MI
- Mona Mostafa Mohamed, Ph.D., Cairo University, Cairo, Egypt
- Christoph Peters, M.D. and Thomas Reinheckel, M.D., Institute of Molecular Medicine and Cell Research, Albert-Ludwigs-Universitat Freiburg, Germany
- John Reiners, Ph.D., Environmental Health Sciences Center for Cellular and Molecular Toxicology with Human Application, Wayne State University, Detroit, MI
- Jeffrey Smith, Ph.D., Burnham Institute, La Jolla, CA
- Boris Turk, Ph.D., Jozef Stefan Institute, Ljubljana, Slovenia
Selected Recent Publications
- Mohamed, M.M. and Sloane, B.F.: Cysteine cathepsins: multifunctional enzymes in cancer. Nature Rev. Cancer 6: 764-775, 2006. PMID: 16990854
- Acuff, H.B., Sinnamon, M., Fingleton, B., Boone, B., Levy, S.E., Chen, X., Pozzi, A., Carbone, D.P., Schwartz, D.R., Moin, K., Sloane, B.F. and Matrisian, M.M.: Analysis of host- and tumor-derived proteinases using a custom dual species microarray reveals a protective role for stromal matrix metalloproteinase 12 in non-small cell lung cancer. Cancer Res. 66: 7968-7975, 2006. PMID: 16912171
- Schwartz, D.R., Moin, K., Yao, B., Matrisian, L.M., Coussens, L.M., Bugge, T.H., Fingleton, B., Acuff, H.B., Sinnamon, M., Nassar, H., Platts, A., Krawetz, S.A., Linebaugh, B.E. and Sloane, B.F.: Hu/Mu ProtIn oligonucleotide microarray: dual species array for profiling protease, protease inhibitor gene expression in tumors and their microenvironment. Mol Cancer Res 5: 443-454, 2007. PMID: 17510311
- Li, Q., Mullins, S.R., Sloane, B.F. and Mattingly, R.R.: p21-activated kinase 1 coordinates aberrant cell survival and pericellular proteolysis in a three-dimensional culture model for premalignant progression of human breast cancer. Neoplasia 10: 314-328, 2008. PMID: 18392133
- Jedeszko, C., Sameni, M., Olive, M.B., Moin, K. and Sloane, B.F.: Visualizing protease activity in living cells: from 2D to 4D. Current Protocols Cell Biol. 39: 4.20.1-4.20.15, 2008. PMID: pending
Search PubMed for publications from the Sloane Lab
Links:
http://www.protease.org/
http://cdmrp.army.mil/bcrp/coeawards.htm
Avon Foundation International Scholars in Training
http://www.burnham.org/default.asp?contentID=81
http://nihroadmap.nih.gov/buildingblocks/technologycenters/
http://bioweb2.bio.uea.ac.uk/cancerdegradome/welcome.html
http://www.med.wayne.edu/mirl/
http://www.karmanos.org
http://www.iehs.wayne.edu/ehs_center.html
http://www.ssim.eng.wayne.edu/
