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2016 Scientific Report

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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 his postdoctoral study with Harold Varmus, Dr. Williams joined VARI as a Scientific Investigator in July 1999. He is now a Professor and the Director of the Center for Cancer and Cell Biology. STAFF CASSIE DIEGEL, B.S. NICOLE ETHEN, B.S. DIANA LEWIS, A.S. MITCH MCDONALD, B.S. ALEX ZHONG, PH.D. STUDENTS CHERYL CHRISTIE, B.S. CASEY DROSCHA, B.S. JOHAN LEE JON LENSING KEVIN MAUPIN, B.A., B.S. AGNI NAIDU, B.S. RESEARCH INTERESTS Our laboratory is interested in understanding how alterations in the Wnt signaling pathway cause human disease. Wnt signaling is a process, conserved throughout evolution, that functions in the differentiation of most tissues. Given its central role in growth and differentiation, it is not surprising that alterations in the Wnt pathway are among the most common events associated with human cancer. In addition, other human diseases including osteoporosis, cardiovascular disease, and diabetes have been linked to altered regulation of this pathway. A specific focus of our work is characterizing the role of Wnt signaling in bone formation. Our interest is not only in normal bone development but also in understanding whether aberrant Wnt signaling plays a role in the metastasis of some common cancers (for example, prostate, breast, lung, and renal tumors) to the bone. The long-term goal of this work is to provide insights useful in developing strategies to lessen the morbidity and mortality associated with skeletal metastasis. Wnt signaling in normal bone development 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. To test whether Lrp5 deficiency causes changes in bone density due to aberrant signaling through β-catenin, we created OC-Cre;β-catenin flox/flox mice, which carry an osteoblastspecific deletion of β-catenin. We are addressing how other genetic alterations linked to Wnt/β-catenin signaling affect bone development and osteoblast function. We have generated mice with conditional alleles of Lrp6 and Lrp5 that can be inactivated via Cre-mediated recombination and have used them to show that both Lrp5 and Lrp6 function within osteoblasts to regulate normal bone development and homeostasis. We have also created mice lacking the ability to secrete Wnts from osteoblasts and shown that these mice have extremely low bone mass, establishing that the mature osteoblast is an important source of Wnts. 24 Van Andel Research Institute | Scientific Report

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. Given that 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. Wnt signaling in mammary development and cancer We are addressing the relative roles of Lrp5 and Lrp6 in Wnt1-induced mammary carcinogenesis. We have focused our initial efforts on Lrp5-deficient mice, because they are viable and fertile. 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 also focusing on the mechanisms that underlie the role that Lrp6 plays in mammary development. We are particularly interested in the pathways that may regulate the proliferation of normal mammary progenitor cells, as well as of tumor-initiating cells. Wnt signaling in prostate development and cancer Two hallmarks of advanced prostate cancer are the development of skeletal osteoblastic metastasis and the ability of the tumor cells to become independent of androgen for survival. We have created mice with a prostate-specific deletion of the Apc gene as a disease model. These mice develop fully penetrant prostate hyperplasia by four months of age, and these tumors progress to frank carcinomas by seven months. We have found that these tumors initially regress under androgen ablation but show signs of androgen-independent growth some months later. Genetically engineered mouse models of bone disease We have also focused on developing mouse models of osteoarthritis and of fracture repair. In addition, we are interested in identifying novel genes that play key roles in skeletal development and maintenance of bone mass. For example, current work is focused on the role of galectin-3, a member of the lectin family, in this context. RECENT PUBLICATIONS Schumacher, Cassie A., Danese M. Joiner, Kennen D. Less, Melissa Oosterhouse Drewry, and Bart O. Williams. 2016. Characterization of genetically engineered mouse models carrying Col2a1-cre-induced deletions of Lrp5 and/or Lrp6. Bone Research 4: 15042. Williams, Bart O. 2016. Genetically engineered mouse models to evaluate the role of Wnt secretion in bone development in homeostasis. American Journal of Medical Genetics C 172(1): 24–26. Valkenburg, Kenneth C., Galen Hostetter, and Bart O. Williams. 2015. Concurrent hepsin overexpression and adenomatous polyposis coli deletion causes invasive prostate carcinoma in mice. The Prostate 75(14): 1579–1585. Zhong, Zhendong, A., Juraj Zahatnansky, John Snider, Emily Van Wieren, Cassandra R. Diegel, and Bart O. Williams. 2015. Wntless spatially regulates bone development through β-catenin-dependent and independent mechanisms. Developmental Dynamics 244(10): 1347–1355. Zhong, Zhendong A., Anderson Peck, Shihong Li, Jeff VanOss, John Snider, Casey J. Droscha, TingTung A. Chang, and Bart O. Williams. 2015. 99m Tc-Methylene diphosphonate uptake at injury site correlates with osteoblast differentiation and mineralization during bone healing in mice. Bone Research 3: 15013. CENTER FOR CANCER AND CELL BIOLOGY 25

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