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2015 Scientific Report

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Van Andel Research

Van Andel Research Institute | Scientific Report 2015 George F. Vande Woude, Ph.D. Laboratory of Molecular Oncology Dr. Vande Woude received his M.S. and Ph.D. degrees from Rutgers University. In 1972, he joined the National Cancer Institute as head of the Human Tumor Studies and Virus Tumor Biochemistry sections. In 1983, he became director of the Advanced Bioscience Laboratories–Basic Research Program at the Frederick Cancer Research and Development Center, a position he held until 1998. From 1995, Dr. Vande Woude first served as special advisor to the director, and then as director, of the Division of Basic Sciences at NCI. In 1999, he was recruited as the founding Director of VARI. In 2009, Dr. Vande Woude stepped down as Director while retaining his leadership of the Laboratory of Molecular Oncology as a Distinguished Scientific Fellow and Professor. Dr. Vande Woude is a member of the National Academy of Sciences (1993) and a Fellow of the American Association for the Advancement of Science (2013). From left, standing: Gao, Kang, Koo, Yerrum; seated: Essenburg, Vande Woude, Kaufman Staff Curt Essenburg, B.S. Chongfeng Gao, Ph.D. Liang Kang, B.S. Dafna Kaufman, M.S. Kay Koo Yanli Su, A.M.A.T. Smitha Yerrum, M.S. Adjunct Faculty Brian Cao, M.D. Henry B. Skinner, Ph.D. 32

Vande Woude I am pleased to report that in the past year, three senior scientists from my lab—Drs. Yu-Wen Zhang, Carrie Graveel, and Qian Xie—were promoted to the position of Research Assistant Professor, an independent leadership position at VARI. Drs. Zhang, Graveel, and Xie joined my laboratory as postdoctoral fellows in the early 2000s, and it has been a privilege to mentor them over the years as they have grown and developed their unique scientific paths. Each one has demonstrated outstanding research abilities that have contributed tremendously to the Institute and toward fulfilling the VARI mission as a whole. The creativity, broad knowledge, and unique experiences of these scientists have led to many important publications and professional collaborations with scientists around the globe. I couldn’t be more proud of the accomplished colleagues that they have become, and I wish them continued success on their respective journeys to scientific discovery. To learn more about their research projects and current interests, please see their individual pages. Research Interests 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, the Vande Woude lab has focused on investigating the paramount role these molecules play in malignant progression and metastasis. As part of the ongoing effort to further our understanding of this signaling system, the lab focuses 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 animal research models that are 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 of an invasive phenotype requires a breakdown of intercellular junctions with neighboring cells, a process termed the epithelial-to-mesenchymal transition (E-MT). Upon arriving at secondary sites, the mesenchymal cells revert to an epithelial phenotype via a mesenchymal-to-epithelial transition (M-ET). Human carcinoma tissues and cells typically show extensive heterogeneity in both phenotype and genotype, suggesting a role for genetic instability in cell type determination. To test this possibility, we have developed methods to continually 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 further showed that these changes dictated the expression of specific genes, which in E-MT events are mesenchymal and in M-ET events are epithelial. Our results suggest that chromosome instability can provide the diversity of gene expression needed for tumor cells to switch phenotype. 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 the 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 preclinical tool for in vivo study of MET-dependent cancers and is used to evaluate treatment strategies that aim to target this pathway. 33

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