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2016 Scientific Report

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GEORGE F. VANDE WOUDE,

GEORGE F. VANDE WOUDE, PH.D. STAFF CHONGFENG GAO, PH.D. LIANG KANG, B.S. KAY KOO DAFNA KAUFMAN, M.S. BEN STAAL, M.S. Dr. Vande Woude received his M.S. and Ph.D. degrees from Rutgers University. He joined the National Cancer Institute in 1972, becoming the director of the ABL–Basic Research Program in 1983, and then director of the Division of Basic Sciences in 1998. In 1999, he became the founding Director of VARI. In 2009, he stepped down as Director while retaining his laboratory as a Distinguished Scientific Fellow and Professor. He is a member of the National Academy of Sciences (1993) and a Fellow of the American Association for the Advancement of Science (2013). RESEARCH INTERESTS ADJUNCT FACULTY BRIAN CAO, M.D. HENRY B. SKINNER, PH.D. MET is overexpressed in many types of human cancer, and its expression correlates with aggressive disease and poor prognosis (visit http://www.vai.org/met/). Since discovering the MET receptor tyrosine kinase and its ligand, hepatocyte growth factor (HGF/SF), in the mid 1980s, our lab has focused on investigating the paramount role these molecules play in malignant progression and metastasis. As part of our ongoing effort, we focus on the mechanisms responsible for tumor progression under the hypothesis that phenotypic switching and chromosome instability can drive tumor progression. In addition, we continue to develop and characterize novel research models to be used in preclinical evaluation of new inhibitors that target MET in a variety of human cancers. Tumor phenotypic switching: mechanism and therapeutic implications In human carcinomas, the acquisition by cells of an invasive phenotype, a process termed the epithelial-to-mesenchymal transition (E-MT), requires a breakdown of intercellular junctions with neighboring cells. Upon arriving at secondary sites, a few of the mesenchymal cells revert to an epithelial phenotype via a mesenchymal-to-epithelial transition (M-ET). We have implicated genetic instability in cell type determination and we have developed methods to isolate phenotypic variants from epithelial or mesenchymal subclones of carcinoma cell lines. We have explored the signal pathway underlying E-MT/M-ET phenotypic switching by gene expression analysis, spectral karyotyping (SKY), and fluorescent in situ hybridization (FISH). We found that changes in chromosome content are associated with phenotypic switching. We have further shown that these changes dictate the expression of specific genes, which in E-MT events are mesenchymal related and in M-ET events are epithelial related. Our results suggest that chromosome instability can provide the diversity of gene expression needed for tumor cells to switch phenotype. 22 Van Andel Research Institute | Scientific Report

In vivo research models: model development and preclinical treatment evaluation Anti-cancer therapy based on blocking the HGF–Met signaling pathway has emerged as an important goal of pharmaceutical research. One of the limitations of studying the altered Met–HGF/SF signaling of human cancers grafted in mouse models has been that the murine HGF/SF protein has a low affinity for human MET. To overcome this, our lab developed a transgenic human HGF-SCID mouse model (hHGFtg-SCID), which generates a human-compatible HGF/SF protein and thus allows for the propagation of human tumors. This model has proven to be a valuable tool for in vivo testing of MET-dependent cancers and is used to evaluate treatment strategies aimed at targeting this pathway. RECENT PUBLICATIONS Johnson, Jennifer, Maria Libera Ascierto, Sandeep Mittal, David Newsome, Liang Kang, Michael Briggs, Kirk Tanner, Francesco M. Marincola, Michael E. Berens, George F. Vande Woude, et al. 2015. Genomic profiling of a hepatocyte growth factor– dependent signature for MET-targeted therapy in glioblastoma. Journal of Translational Medicine 13: 306. CENTER FOR CANCER AND CELL BIOLOGY 23

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