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2009 Scientific Report

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Van Andel Research

Van Andel Research Institute | Scientific Report Project 3: Role of CD82 in prostate cancer metastasis Death from prostate cancer is due to the development of metastatic disease, which is difficult to control. CD82/KAI1 is a metastasis suppressor gene whose expression is specifically lost in metastatic cancer, but not in primary tumors. Interestingly, CD82/KAI1 (a member of the tetraspanin family) is known to associate with both integrins and receptor tyrosine kinases. Our goal has been to determine how loss of CD82/KAI1 expression promotes metastasis by studying the role of CD82/KAI1 in integrin and receptor tyrosine kinase crosstalk. Mechanism of CD82 suppression of c-Met We have found that reexpression of CD82/KAI1 in metastatic tumor cells suppresses laminin-specific migration and invasion via suppression of both integrin- and ligand-induced activation of c-Met. Thus, CD82/KAI1 normally acts to regulate signaling through c-Met; upon CD82 loss in tumor cells, signaling through c-Met is increased, leading to increased invasion. We are currently determining the mechanism by which CD82/KAI1 down-regulates c-Met signaling. So far our studies indicate that c-Met and CD82 do not directly interact, and CD82 may act to suppress c-Met signaling indirectly by dispersing the c-Met aggregates on metastatic tumor cells into monomers, thus blocking signaling. We have generated mutants of CD82 to determine which part of the CD82 molecule is required for suppression of c-Met activity. In addition, we have determined that reexpression of CD82 in tumor cells induces a physical association between CD82 and a related family member, CD9. Loss of CD9 prevents CD82 from suppressing c-Met. We are currently determining whether CD82/CD9 association with integrins is required to suppress c-Met. CD82 control of metastasis and c-Met activation in vivo We have initiated several mouse studies to determine the mechanism by which loss of CD82 promotes metastasis in vivo. The ability of DU145 prostate cancer cells to metastasize depends on activation of c-Met. Using transgenic SCID mice that express the human version of HGF (only human HGF will activate human c-Met), we have been able to demonstrate that DU145 tumor cells will metastasize only in the HGF/SCID mice, but not in regular SCID mice. Under these conditions, reexpression of CD82 completely suppresses metastasis and there is a dramatic reduction in c-Met activity in the tumors. Mutants that no longer suppress c-Met activity in vitro will be used to demonstrate that they are also no longer capable of suppressing metastasis in the HGF/SCID mice. In addition, we have generated mice with conditional loss of CD82 expression in the prostate, as well as mice with complete CD82 loss in all tissues. These mice have been crossed with mice that develop only primary tumors (Pten conditional) in order to determine if the loss of CD82 is sufficient to induce prostate cancer metastasis. The mice are currently aging and being monitored for the development of tumors and metastases. Future studies will include back-crossing to alternative backgrounds and crossings with other tumor-prone mice. Recent Publications Miranti, C.K. 2009. Controlling cell surface dynamics and signaling: how CD82/KAI1 suppresses metastasis. Cellular Signalling 21(2): 196–211. From left: Miranti, Schulz, Spotts, Lamb, Saari, Tesfay, Park, Zarif 38

VARI | 2009 James H. Resau, Ph.D. Division of Quantitative Sciences Laboratory of Analytical, Cellular, and Molecular Microscopy Laboratory of Microarray Technology Laboratory of Molecular Epidemiology Dr. Resau received his Ph.D. from the University of Maryland School of Medicine in 1985. He has been involved in clinical and basic science imaging and pathology-related research since 1972. Between 1968 and 1994, he was in the U.S. Army (active duty and reserve assignments) and served in Vietnam. From 1985 until 1992, Dr. Resau was a tenured faculty member at the University of Maryland School of Medicine, Department of Pathology. Dr. Resau was the Director of the Analytical, Cellular and Molecular Microscopy Laboratory in the Advanced BioScience Laboratories–Basic Research Program at the National Cancer Institute, Frederick Cancer Research and Development Center, Maryland, from 1992 to 1999. He joined VARI as a Special Program Senior Scientific Investigator in June 1999 and in 2003 was promoted to Deputy Director. In 2004, Dr. Resau assumed as well the direction of the Laboratory of Microarray Technology to consolidate the imaging and quantification of clinical samples in a CLIAtype research laboratory program. In 2005, Dr. Resau was made the Division Director of the quantitative laboratories (pathology-histology, microarray, proteomics, epidemiology, and bioinformatics), and in 2006 he was promoted to Distinguished Scientific Investigator. Staff Students Visiting Scientist Eric Kort, M.D. Sok Kean Khoo, Ph.D. Brendan Looyenga, Ph.D. Bree Berghuis, B.S., HTL (ASCP), QIHC Eric Hudson, B.S. Angie Jason, B.S. Natalie Kent, B.S. Ken Olinger, B.S. Kristin VandenBeldt, B.S. JC Goolsby, A.A. Danielle Burgenske, B.S. Kevin Coalter, B.S. Pete Haak, B.S. Kimberly Paquette, B.S. Sarah Barney Janell Carruthers Katsuo Hisano Rebecca O’Leary Sara Ramirez Allison Vander Ploeg Katie Van Drunen Yair Andegeko 39

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