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2007 Scientific Report

  • Text
  • Report
  • Institute
  • Protein
  • Signaling
  • Tumor
  • Michigan
  • Molecular


VARI | 2007 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. 39 Staff Laboratory Staff Mathew Edick, Ph.D. Suganthi Sridhar, Ph.D. Kristin Saari, M.S. Lia Tesfay, M.S. Laura Lamb, B.S. Veronique Schulz, B.S. Susan Spotts, B.S. Students Students Eric Graf Gary Rajah Visiting Scientists

Van Andel Research Institute | Scientific Report Research Interests Our laboratory is interested in the mechanisms by which integrin receptors, interacting with the extracellular matrix (ECM), 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 ECM proteins. By interacting with the ECM, integrins stimulate intracellular signaling transduction pathways to 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 40 Tumors that develop from 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 at the time of diagnosis have androgen-dependent and organ-confined prostate cancer are relatively easy to cure through radical prostatectomy or localized radiotherapy, but patients with aggressive and metastatic disease have fewer options. Androgen ablation can significantly reduce the tumor burden in the latter 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, α3β1 and α6β4 integrins on epithelial cells bind to the ECM protein laminin 5 in the basement membrane. In tumor cells, however, the α3 and β4 integrin subunits disappear—as does laminin 5—and the tumor cells express primarily α6β1 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 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.

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