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2018 Scientific Report

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Center for Cancer and

Center for Cancer and Cell Biology BART O. WILLIAMS, Ph.D. Dr. Williams received his Ph.D. in biology from Massachusetts Institute of Technology in 1996, where he trained with Tyler Jacks. Following postdoctoral study with Harold Varmus, he joined VARI in July 1999. He is now a Professor and the Director of the Center for Cancer and Cell Biology. STAFF Cassie Diegel, B.S. Gabrielle Foxa, B.S. Mitch McDonald, B.S. Megan Michalski, D.D.S, Ph.D. Michelle Minard, B.S. Alex Zhong, Ph.D. STUDENTS Isaac Izaguirre Katie Krajnak, M.S. Adam Racette RESEARCH INTERESTS We are studying how alterations in the WNT signaling pathway cause human disease. Given that WNT signaling functions in the growth and differentiation of most tissues, it is not surprising that changes in this pathway are among the most common events in human cancer. Other diseases, including osteoporosis, cardiovascular disease, and diabetes, have also been linked to it. Our work includes studying the role of WNT signaling in normal bone formation and in the metastasis of cancer to the bone. We are also interested in identifying the genes that play key roles in skeletal development and maintenance of bone mass. Mutations in LRP5, a WNT receptor, have been causally linked to alterations in human bone development. We have characterized a mouse strain deficient in LRP5 and have shown that it recapitulates the low-bone-density phenotype seen in human patients who have that deficiency. We have further shown that mice carrying mutations in both LRP5 and the related LRP6 protein have even more-severe defects in bone density. We are also examining the effects on normal bone development and homeostasis of chemical inhibitors of the enzyme Porcupine, which is required for the secretion and activity of all WNTs. Because such inhibitors are currently in human clinical trials for treatment of several tumor types, their side effects related to the lowering of bone mass must be evaluated. We are addressing the relative roles of LRP5 and LRP6 in WNT1-induced mammary carcinogenesis. A deficiency in LRP5 dramatically inhibits the development of mammary tumors, and a germline deficiency in LRP5 or LRP6 results in delayed mammary development. We are particularly interested in the pathways that may regulate the proliferation of normal mammary progenitor cells, as well as of tumorinitiating cells. In another project, we are studying the development of skeletal osteoblastic metastasis from prostate cancer and the ability of the tumor cells to become independent of androgen for survival. Finally, part of our work focuses on developing genetically engineered mouse models, for example, models of osteoarthritis. Nolan Redetzke 14 | VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT

NING WU, Ph.D. Dr. Wu received her Ph.D. from the Department of Biochemistry of the University of Toronto in 2002. She joined VARI in 2013 as an Assistant Professor. RESEARCH INTERESTS Many human diseases, such as diabetes, neurodegeneration, cancer, and heart problems, come with old age. Our laboratory studies the interface between cellular metabolism and signal transduction, focusing on key steps in glucose and lipid metabolism in order to understand the ways that nutrients can delay aging effects and thus postpone the onset of disease. STAFF Holly Dykstra, B.S. Althea Waldhart, B.S. Jeanie Wedberg, A.S. Glucose is a vital, highly regulated metabolite in the human body. Its concentration is tightly controlled within a narrow range by factors secreted from several tissues. Too much glucose uptake leads to systemic problems that partly stem from oxidative stress generated by the mitochondria. Our lab examines the mechanism by which cells control glucose uptake, what regulates the flux from glucose to unwanted lipid accumulation, and how mitochondrial function is affected by glucose concentration. At the atomic scale, we employ cryo-electron microscopy to solve the structures of transporter proteins and their regulators. At the cellular level, we investigate how cells respond to metabolic stress. At the organism level, we integrate the cellular response with systemic response to understand how diet can modify and curb unwanted oxidative damage. This research will provide better insight into the relationship between diet and health and open the possibility of individualized diet recommendations to delay aging effects. VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT | 15

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