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2002 Scientific Report

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Tumor Metastasis and

Tumor Metastasis and Angiogenesis Laboratory Craig P. Webb, Ph.D. Dr. Webb received his Ph.D. in cell biology from the University of East Anglia, England, in 1995. He then served as a Postdoctoral Fellow in the laboratory of George Vande Woude in the Molecular Oncology Section of the Advanced BioScience Laboratories–Basic Research Program at the National Cancer Institute–Frederick Cancer Research and Development Center, Maryland (1995–1999). Dr. Webb joined VARI as a Scientific Investigator in October 1999. Staff Jeremy Miller, Ph.D. David Monsma, Ph.D. Emily Eugster, M.S. Laboratory Members Guest worker Lonson Barr, D.O. Students Kelly Ballast, B.S. Donald Chaffee Meghan Sheehan Research Projects T umor metastasis, the process by which cancer spreads throughout a host to secondary tissues, accounts for the majority of cancer-related mortalities. The active recruitment of tumor vasculature, generally termed angiogenesis, is integral to both tumor growth and metastasis. Our laboratory focuses on identifying the key cellular and molecular determinants of metastatic progression in order to improve our conceptual understanding of the process, with the goal of developing diagnostics and therapeutics that target this most damaging aspect of cancer. Our lab currently utilizes various systems to study metastasis and angiogenesis both in vitro and in vivo. For example, we have previously described murine cell lines that display various metastatic propensities after ectopic expression of effector domain mutants of the ras oncogene. These mutants are particularly useful, because they differentially activate signaling pathways downstream of Ras and hence can be used to dissect the pathways and subsequent genetic/epigenetic events that mediate metastasis in this experimental setting. In tandem with our fluorescent imaging capabilities, we are now able to follow individual tumor cells as they undergo the various stages of metastatic spread. We are using these imaging strategies with other mouse models to follow the progression of metastases, such as metastasis to the liver after the formation of primary pancreatic carcinomas. Of particular importance, we are beginning to determine the factors that contribute to metastatic dormancy, a frequent occurrence in which individual metastatic cells within secondary tissues fail to progress to macroscopic disease, but instead lie dormant until a later time. Very little is known about the factors that contribute to this phenomenon, yet this aspect of metastasis likely accounts for the minimal residual disease and metastatic relapse observed in many patients. We are now using a combination of some state-of-the-art technologies, including laser capture microdissection, proteomics, and gene chip arrays, to integrate the genomic and proteomic events that occur during tumor-host interactions throughout the metastatic process in mouse models and human patient material. In this fashion, we have identified a number of candidate genes and proteins that appear to play prominent roles in metastasis to specific secondary sites. Our lab has now begun to systematically validate these targets for their precise functional roles. These types of studies will continue to generate essential information about the factors that regulate metastatic progression and will identify diagnostic/therapeutic targets for the future. In collaboration with local clinicians and some industrial partners, we are striving toward the early diagnosis and treatment of malignant disease. 49

External Collaborators Lonson Barr, Donald Kim, Martin Luchtefeld, and Thomas Monroe, Spectrum Health, Grand Rapids, Michigan Yihai Cao, Karolinska Institute, Stockholm, Sweden Ann Chambers, University of Western Ontario, London, Canada Samir Hanash and Gil Omenn, University of Michigan, Ann Arbor Robert Hoffman, Anticancer Inc., San Diego, California Beatrice Knudsen, Cornell University, Ithaca, New York Ken Lipson, SUGEN, Inc., South San Francisco, California Martin McMahon, University of San Francisco, California Anthony Schaeffer, Northwestern University, Evanston, Illinois Bin S. Teh, Baylor College of Medicine, Waco, Texas Annette Thelen, Michigan State University, Lansing Affymetrix, Santa Clara, California Micromass, Beverly, Massachusetts Pharmacia (SUGEN Inc), California Publications Furge, Kyle A., David Kiewlich, Phuong Le, My Nga Vo, Michel Faure, Anthony R. Howlett, Kenneth E. Lipson, George F. Vande Woude, and Craig P. Webb. 2001. Suppression of Ras-mediated tumorigenicity and metastasis through inhibition of the Met receptor tyrosine kinase. Proceedings of the National Academy of Sciences U.S.A. 98(19): 10722–10727. Haddad, Ramsi, Kyle A. Furge, Jeremy C. Miller, Brian B. Haab, J. Schoumans, Bin T. Teh, Lonson Barr, and Craig P. Webb. In press. Genomic profiling and cDNA microarray analysis of human colon adenocarcinoma and associated intraperitoneal metastases reveals consistent cytogenetic and transcriptional aberrations associated with progression of multiple metastases. Applied Genomics and Proteomics. Haddad, Ramsi, and Craig P. Webb. 2001. Hepatocyte growth factor expression in human cancer and therapy with specific inhibitors. Anticancer Research 21(6B): 4243–4252. Webb, Craig P., and George F. Vande Woude. 2002. Met gene. In Wiley Encyclopedia of Molecular Medicine, Haig H. Kazazian, ed. New York: Wiley, pp. 2049–2051. From left to right: Webb, Monsma, Miller, Sheehan, Eugster, Chaffee, Ballast, Barr 50

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