2009 Scientific Report

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Van Andel Research Institute | Scientific Report Bart O. Williams, Ph.D. Laboratory of Cell Signaling and Carcinogenesis Dr. Williams received his B.S. degree from Carroll College in Waukesha, Wisconsin. In 1996, he received his Ph.D. in Biology from the Massachusetts Institute of Technology for studies in the laboratory of Tyler Jacks characterizing mouse models carrying mutations in the Rb and p53 genes. From 1996 to 1999, he was a postdoctoral fellow at the National Institutes of Health in the laboratory of Harold Varmus, former Director of NIH. Dr. Williams joined VARI as a Scientific Investigator in July 1999 and was promoted to Senior Scientific Investigator in 2006. Staff Charlotta Lindvall, M.D., Ph.D. Alex Zhen-Dong Zhong, Ph.D. Cassandra Zylstra Diegel, B.S. Angela Lake, B.S. Ammar Saladhar, B.S. Kyle VanKoevering, B.S. Students Stephanie Berry Sathyanarayanan Elumalai Audrey Sanders Cassie Schumacher 68
VARI | 2009 Research Interests Our laboratory is interested in understanding how alterations in the Wnt signaling pathway cause human disease. Specifically, we have focused our efforts on the functions of the Wnt co-receptors, Lrp5 and Lrp6. Wnt signaling is an evolutionarily conserved process that functions in the differentiation of most tissues within the body. Given its central role in growth and differentiation, it is not surprising that alterations in the pathway are among the most common events associated with human cancer. In addition, several other human diseases, including osteoporosis, cardiovascular disease, and diabetes, have been linked to altered regulation of this pathway. A specific focus of work in our laboratory is characterizing the role of Wnt signaling in bone formation. Our interest is not only from the perspective of normal bone development, but also in trying to understand whether aberrant Wnt signaling plays a role in the predisposition of some common tumor types (for example, prostate, breast, lung, and renal tumors) to metastasize to and grow in 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 the Wnt receptor Lrp5 have been causally linked to alterations in human bone development. We have characterized a mouse strain deficient in Lrp5 and shown that it recapitulates the low-bone-density phenotype seen in human patients who have Lrp5 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 b-catenin, we created mice carrying an osteoblast-specific deletion of b-catenin (OC-cre;b-catenin-flox/flox mice). In collaboration with Tom Clemens of the University of Alabama at Birmingham, we found that alterations of Wnt/b-catenin signaling in osteoblasts lead to changes in the expression of RANKL and osteoprotegerin (OPG). Consistent with this, histomorphometric evaluation of bone in the mice with osteoblast-specific deletions of either Apc or b-catenin revealed significant alterations in osteoclastogenesis. We are addressing how other genetic alterations linked to Wnt/b-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 we are assessing the roles of these genes at different stages of osteoblast differentiation using both OC-cre and Dermo1-cre. Finally, we are working to determine what other signaling pathways may impinge on b-catenin signaling to control osteoblast differentiation and function. Wnt signaling in mammary development and cancer We are also 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 for Lrp5 or Lrp6 results in delayed mammary development. Because Lrp5-deficient mice are viable and fertile, we have focused our initial efforts on these mice. In collaboration with Caroline Alexander’s laboratory, we have found dramatic reductions in the number of mammary progenitor cells in these mice, and we are examining the mechanisms underlying this reduction. We have also found that Lrp6 plays a key role in mammary development, and we are focusing on the mechanisms underlying this unique role. Finally, we are defining the relative roles of b-catenin and mTOR signaling in the initiation and progression of Wnt1-induced mammary tumors. We are particularly interested in the role(s) of these pathways in regulating the proliferation of normal mammary progenitor cells, as well as of tumor-initiating cells. Wnt signaling in metabolic syndrome Several studies have linked mutations in Lrp5 and/or Lrp6 to the development of diabetes, dyslipedemias, and hypertension in humans and mice. We are exploring the roles of these genes in this context by creating mice carrying conditional deletions in hepatocytes or in adipocytes and evaluating their phenotypes. 69
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