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2008 Scientific Report

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Van Andel Research

Van Andel Research Institute | Scientific Report Cindy K. Miranti, Ph.D. Laboratory of Integrin Signaling and Tumorigenesis Dr. Miranti received her M.S. in microbiology from Colorado State University in 1982 and her Ph.D. in biochemistry from Harvard Medical School in 1995. She was a postdoctoral fellow in the laboratory of Joan Brugge at ARIAD Pharmaceuticals, Cambridge, Massachusetts, from 1995 to 1997 and in the Department of Cell Biology at Harvard Medical School from 1997 to 2000. Dr. Miranti joined VARI as a Scientific Investigator in January 2000. She is also an Adjunct Assistant Professor in the Department of Physiology at Michigan State University and an Assistant Professor in the Van Andel Education Institute. Staff Kristin Saari, M.S. Lia Tesfay, M.S. Veronique Schulz, B.S. 38 Students Jelani Zarif, M.S. Laura Lamb, B.S. Susan Spotts, B.S. Erica Bechtel Eric Graf Fraser Holleywood Gary Rajah

VARI | 2008 Research Interests Our laboratory is interested in understanding the mechanisms by which integrin receptors, interacting with the extracellular matrix, regulate cell processes involved in the development and progression of cancer. Using tissue culture models, biochemistry, molecular genetics, and mouse models, we are defining the cellular and molecular events involved in integrin-dependent adhesion and downstream signaling that are important for prostate tumorigenesis and metastasis. Integrins are transmembrane proteins that serve as receptors for extracellular matrix (ECM) proteins. By interacting with the ECM, integrins stimulate intracellular signaling transduction pathways that regulate cell shape, proliferation, migration, survival, gene expression, and differentiation. Integrins do not act autonomously, but “crosstalk” with receptor tyrosine kinases (RTKs) to regulate many of these cellular processes. Studies in our lab indicate that integrin-mediated adhesion to ECM proteins activates epidermal growth factor receptors EGFR/ErbB2 and the HGF/SF receptor c-Met. Integrin-mediated activation of these RTKs is ligand-independent and required for the activation of a subset of intracellular signaling molecules in response to cell adhesion. The prostate gland and cancer Tumors that develop in cells of epithelial origin, i.e., carcinomas, represent the largest tumor burden in the United States. Prostate cancer is the most frequently diagnosed cancer in American men and the second leading cause of cancer death in men. Patients who present at the time of diagnosis with androgen-dependent and organ-confined prostate cancer are relatively easy to cure through radical prostatectomy or localized radiotherapy. However, patients with aggressive and metastatic disease have fewer options. Androgen ablation can significantly reduce the tumor burden in these patients, but the potential for relapse and the development of androgen-independent cancer is high. Currently there are no effective treatments for patients who reach this stage of disease. In the human prostate gland, a3b1 and a6b4 integrins on epithelial cells bind to the ECM protein laminin 5 in the basement membrane. In tumor cells, however, the a3 and b4 integrin subunits disappear—as does laminin 5—and the tumor cells express primarily a6b1 and adhere to a basement membrane containing laminin 10. There is also an increase in expression of the RTKs EGFR and c-Met in the tumor cells. Two fundamental questions in our lab are whether the changes in integrin and matrix interactions that occur in tumor cells are required for or help to drive the survival of tumor cells, and whether crosstalk with RTKs is important for cell survival. Integrins and RTKs in prostate epithelial cell survival How integrin engagement of different ECMs regulates survival pathways in normal and tumor cells is poorly understood. We have previously demonstrated that integrin-induced activation of EGFR in normal primary prostate epithelial cells is required for survival of these cells on their endogenous matrix, laminin 5. The ability of EGFR to support integrin-mediated cell survival on laminin 5 is mediated through a3b1 integrin and requires signaling downstream to Erk. Surprisingly, we found that the death induced by inhibition of EGFR in normal primary prostate cells is not mediated through or dependent on classical caspasemediated apoptosis. The presence of an autophagic survival pathway, regulated by adhesion to matrix, prevents the induction of caspases when EGFR is inhibited. Suppression of autophagy is sufficient to induce caspase activation and apoptosis in laminin 5–adherent primary prostate epithelial cells. Thus, adhesion of normal cells to matrix regulates survival through at least two mechanisms, crosstalk with EGFR and Erk and maintenance of an autophagic survival pathway. We have begun studies to determine how integrins regulate cell survival through autophagy. When we block expression of the RTK c-Met in primary prostate epithelial cells adherent to laminin 5, they also die. In this case death is due to classical caspase-mediated apoptosis. Since autophagy must be inhibited in these cells to induce apoptosis, these results suggest that c-Met may regulate autophagy. Future studies in our lab are aimed at deciphering this pathway and determining how this pathway is altered during tumor progression. 39

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