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2013 Scientific Report

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VARI | 2013 Research Interests Our laboratory is interested in understanding how alterations in the Wnt signaling pathway cause human disease. Wnt signaling is an evolutionarily conserved process that functions in the differentiation of most tissues within the body. Wnt proteins initiate several signaling pathways, including one that results in the activation of the b-catenin protein and its downstream signaling targets. 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, neurodegenerative diseases, and diabetes have been linked to altered regulation of this pathway. Our main approach toward gaining insights into the mechanisms of Wnt signaling in development and disease is to create and characterize genetically engineered mouse models. We have pursued studies in three key areas outlined below. In addition, we are interested in understanding the molecular mechanisms by which specificity is generated by Wnts. Wnt signaling in skeletal development and disease A specific focus of our work is characterizing the role of Wnt signaling in skeletal development and disease. Mutations in the Wnt receptor Lrp5 have been causally linked to alterations in human bone development. Several years ago, we characterized a mouse strain carrying a germline deletion in Lrp5 and found that it recapitulated the low-bone-density phenotype seen in human patients who have a LRP5 deficiency. We further found that mice carrying germline deletions in both Lrp5 and the related Lrp6 protein have even more-severe defects in bone density. We next created mice carrying an osteoblast-specific deletion of b-catenin. Those mice have severely diminished bone mass and elevated osteoclastogenesis associated with changes in the expression of RANKL and osteoprotegerin. Our next step was to create and evaluate mice carrying osteoblastspecific deletions of Lrp6 and Lrp5. We have found that mice carrying deletions in either gene alone have reduced bone mass, and mice lacking both genes in osteoblasts have more-severe phenotypes. More recent studies have focused on gaining insight into the cell type(s) that secrete the Wnts necessary for normal bone development. Our strategy has used mice carrying osteoblast-specific deletions of the Wntless/Gpr177 (Wls) gene. Wls encodes a protein specifically required for secretion of all mammalian Wnts, and a mouse strain carrying a Wls allele that can be conditionally inactivated was developed by our collaborator, Richard Lang. We have generated mice carrying an osteoblast-specific deletion of this gene and found that mature osteoblasts are a crucial source of the Wnts required for normal skeletal development. Current work is also focusing on evaluating the roles of Wnt signaling in osteoarthritis and fracture repair, as well examining how other signaling pathways integrate with Wnt/b-catenin signaling to control osteoblast differentiation and function. Two such examples are the effects of parafibromin on regulating transcriptional outputs through its interaction with b-catenin and the potential role of galectin-3 in this process. 67

Van Andel Research Institute | Scientific Report Wnt signaling in mammary development and cancer Activation of the Wnt signaling pathway has been linked to the development of some types of breast tumors. We are using genetically engineered mouse models to assess the roles of Wnt signaling in mammary development and carcinogenesis. Mice carrying conditional deletions of Lrp5 and / or Lrp6 in mammary epithelial cells have been developed and are being characterized. We are evaluating the role that activation of Wnt signaling plays in establishing and maintaining tumor-initiating cells within the mammary gland. We are also examining the source of Wnts necessary for normal mammary development and for the maintenance of some types of breast tumors. Wnt signaling in prostate development and cancer A hallmark of advanced prostate cancer is the development of skeletal osteoblastic metastases. The association of Wnt signaling with bone growth makes Wnt signaling an attractive candidate for explaining some phenotypes associated with advanced prostate cancer. As a first step to understanding the role of Wnt signaling in prostate carcinogenesis, we have generated mice carrying prostate-epithelial-specific deletion of Apc. We have found that mice carrying conditional deletions induced by either probasin-Cre or Nkx3.1-Cre develop prostate tumors having similar latency and pathology. Further, we are directly examining the role of Wnt signaling by assessing the effects of inhibiting the secretion of Wnts in models of skeletal metastases. We also have a specific interest in examining the role of Wnt5a in this process. Recent Publications Joiner, Danese M., Jiyuan Ke, Zhendong Zhong, H. Eric Xu, and Bart O. Williams. 2013. LRP5 and LRP6 in development and disease. Trends in Endocrinology and Metabolism 24(1): 31–39. Fortin, Shannon P., Matthew J. Ennis, Cassie A. Schumacher, Cassandra R. Zylstra-Diegel, Bart O. Williams, Julianna T.D. Ross, Jeffrey A. Winkles, Joseph C. Loftus, Marc H. Symons, and Nhan L. Tran. 2012. Cdc42 and the guanine nucleotide exchange factors Ect2 and Trio mediate Fn14-Rac1-induced migration and invasion of glioblastoma cells. Molecular Cancer Research 10(7): 958–968. Ke, Jiyuan, Chenghai Zhang, Kaleeckal G. Harikumar, Cassandra R. Zylstra-Diegel, Liren Wang, Laura E. Mowry, Laurence J. Miller, Bart O. Williams, and H. Eric Xu. 2012. Modulation of b-catenin signaling by glucagon receptor activation. PLoS One 7(3): e33676. Li, Yi, Andrea Ferris, Brian C. Lewis, Sandra Orsulic, Bart O. Williams, Eric C. Holland, and Stephen H. Hughes. 2012. The RCAS/TVA somatic gene transfer method in modeling human cancer. In Genetically Engineered Mice for Cancer Research, Jeffrey E. Green and Thomas Ried, eds. Berlin: Springer Verlag, pp. 83–112. Zhong, Zhendong., and Bart O. Williams. 2012. Integration of cellular adhesion and Wnt signaling: interactions between N-cadherin and LRP5 and their role in regulating bone mass. Journal of Bone and Mineral Research 27(9): 1849–1851. Zhong, Zhendong, Bart O. Williams, and Matthew R. Steensma. 2012. The activation of b-catenin by Gas contributes to the etiology of phenotypes seen in fibrous dysplasia and McCune-Albright syndrome. IBMS BoneKEy 9: 113. Zhong, Zhendong, Cassandra R. Zylstra-Diegel, Cassie A. Schumacher, Jacob J. Baker, April C. Carpenter, Sujata Rao, Wei Yao, Min Guan, Jill A. Helms, Nancy E. Lane, et al. 2012. Wntless functions in mature osteoblasts to regulate bone mass. Proceedings of the National Academy of Sciences U.S.A. 109(33): E2197–E2204. 68

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