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2013 Scientific Report

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VARI | 2013 Tumor phenotypic switching: mechanism and therapeutic implications In human carcinomas, acquisition of an invasive phenotype requires a breakdown of intercellular junctions with neighboring cells, a process termed the epithelial-to-mesenchymal transition (E-MT). Paradoxically, metastatic carcinomas often exhibit an epithelial phenotype, leading to the hypothesis that E-MT is a transient process induced by microenvironmental factors. Upon arriving at secondary sites, the mesenchymal cells revert to an epithelial phenotype (mesenchymal-to-epithelial transition; M-ET). Typically, human carcinoma tissues and cells exhibit 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 isolate phenotypic variants from epithelial or mesenchymal subclones of carcinoma cell lines, as well as to identify subclones that switch phenotypically. 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. Recent Publications Gherardi, Ermanno, Walter Birchmeier, Carmen Birchmeier, and George Vande Woude. 2012. Targeting MET in cancer: rationale and progress. Nature Reviews Cancer 12(2): 89–103. Kentsis, Alex, Casie Reed, Kim L. Rice, Takaomi Sanda, Scott J. Rodig, Eleni Tholouli, Amanda Christie, Peter J.M. Valk, Ruud Delwel, Vu Ngo, et al. 2012. Autocrine activation of the MET receptor tyrosine kinase in acute myeloid leukemia. Nature Medicine 18(7): 1118–1122. Nickoloff, Brian J., and George Vande Woude. 2012. Hepatocyte growth factor in the neighborhood reverses resistance to BRAF inhibitor in melanoma. Pigment Cell & Melanoma Research 25(6): 758–761. Xie, Qian, George F. Vande Woude, and Michael E. Berens. 2012. RTK inhibition: looking for the right pathways toward a miracle. Future Oncology 8(11): 1397–1400. Zhang, Yu-Wen, Ben Staal, Karl J. Dykema, Kyle A. Furge, and George F. Vande Woude. 2012. Cancer-type regulation of MIG-6 expression by inhibitors of methylation and histone deacetylation. PLoS One 7(6): e38955. Xie, Qian, Robert Bradley, Liang Kang, Julie Koeman, Maria Libera Ascierto, Andrea Worschech, Valeria De Giorgi, Ena Want, Lisa Kefene, Yanli Su, et al. 2011. Hepatocyte growth factor (HGF) autocrine activation predicts sensitivity to MET inhibition in glioblastoma. Proceedings of the National Academy of Sciences U.S.A. 109(2): 570–575. Xie, Qian, Robert Wondergem, Yuehai Shen, Greg Cavey, Jiyuan Ke, Ryan Thompson, Robert Bradley, Jennifer Daugherty- Holtrop, Yong Xu, Edwin Chen, et al. 2011. Benzoquinone ansamycin 17AAG binds to mitochondrial voltage-dependent anion channel and inhibits cell invasion. Proceedings of the National Academy of Sciences U.S.A. 108(10): 4105–4110. 59

Craig P. Webb, Ph.D. Laboratory for Translational Medicine Dr. Webb received his Ph.D. in cell biology from the University of East Anglia, England, in 1995. From 1995 to 1999, he was a postdoctoral fellow with George Vande Woude at the National Cancer Institute–Frederick Cancer Research and Development Center, Maryland. Dr. Webb joined VARI in October 1999 and was promoted to Professor in 2008. He is also co- Director of the Pediatric Cancer Translational Research Program. From left: Webb, Moon, Popkie, Davidson, Eugster, Dylewski, Orey, Monsma, Scott, Montroy, Monks, Cherba, Mooney Staff Students Visiting Scientists Adjunct Faculty David Cherba, Ph.D. Paula Davidson, M.S. Dawna Dylewski, B.S. Emily Eugster, M.S. Noel Monks, Ph.D. David Monsma, Ph.D. Rob Montroy, B.E. Lori Moon, M.B.A. Anthony Popkie, Ph.D. Stephanie Scott, B.S. Marie Mooney, M.S. Stephen Orey, B.S. Jessica Foley, M.D. Eric Kort, M.D. Debra Weist, Ph.D. Eric Lester, M.D. Laurence McCahill, M.D. 60

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