The candidate is an MD-PhD who completed clinical training in dermatology in June 2005 and is now pursuing basic science research with the goal of becoming an independent physician-scientist. The research is being performed under the sponsorship of Dr. Randall T. Moon at the University of Washington. The Moon laboratory studies the role of the Wnt signaling pathway in embryonic development and human disease using several model systems, including zebrafish and frogs. The proposed training will prepare the candidate for a career as an independent investigator in skin biology and cutaneous oncology, with a focus on cell biology, cell motility and signal transduction. The incidence of malignant melanoma is increasing faster than that of any other cancer. The lack of effective therapies for metastatic disease reflects our limited understanding of the progression of melanoma and metastasis. Recent studies have implicated the Wnt signaling pathway as an important regulator of both melanoma progression as well as the development of metastatic disease. Wnt's are secreted proteins that bind cell surface receptors to trigger a series of regulated intracellular events that mediate functions including cell growth, cell differentiation, cell adhesion and cell motility. This proposal aims to identify proteins that are important in the regulation of cell motility by the Wnt pathway using a melanoma cell line that exhibits increased motility upon Wnt expression. The proposal will utilize techniques with demonstrated feasibility to test known Wnt proteins for their effects on melanoma cell motility. Next, new candidate Wnt proteins will be identified by the purification of Wnt-related protein complexes in melanoma cells using another established technique. These new proteins will also be tested for effects on cell motility. The issue of molecular heterogeneity seen in melanoma progression will be addressed by evaluating proteins with validated functional significance in the context of different melanoma cell lines, complemented by evaluation of protein expression in patient melanoma samples. Together, these studies will help elucidate the mechanisms underlying the regulation of cell motility by Wnt signaling in the context of malignant melanoma, with the ultimate goal of uncovering protein targets that could serve as biomarkers for prognosis and/or targets for therapeutic manipulation. ? ? ?
| Arensman, M D; Kovochich, A N; Kulikauskas, R M et al. (2014) WNT7B mediates autocrine Wnt/?-catenin signaling and anchorage-independent growth in pancreatic adenocarcinoma. Oncogene 33:899-908 |
| James, Richard G; Bosch, Katherine A; Kulikauskas, Rima M et al. (2013) Protein kinase PKN1 represses Wnt/?-catenin signaling in human melanoma cells. J Biol Chem 288:34658-70 |
| Zimmerman, Zachary F; Moon, Randall T; Chien, Andy J (2012) Targeting Wnt pathways in disease. Cold Spring Harb Perspect Biol 4: |
| Biechele, Travis L; Kulikauskas, Rima M; Toroni, Rachel A et al. (2012) Wnt/?-catenin signaling and AXIN1 regulate apoptosis triggered by inhibition of the mutant kinase BRAFV600E in human melanoma. Sci Signal 5:ra3 |
| White, Bryan D; Chien, Andy J; Dawson, David W (2012) Dysregulation of Wnt/ýý-catenin signaling in gastrointestinal cancers. Gastroenterology 142:219-32 |
| Tavakkol, Zarry; Keller, Jesse J; Furmanczyk, Paul S et al. (2012) Germline mutation in MSH6 associated with multiple malignant neoplasms in a patient With Muir-Torre syndrome. J Clin Oncol 30:e195-8 |
| Biechele, Travis L; Camp, Nathan D; Fass, Daniel M et al. (2010) Chemical-genetic screen identifies riluzole as an enhancer of Wnt/?-catenin signaling in melanoma. Chem Biol 17:1177-82 |
| Chien, Andy J; Conrad, William H; Moon, Randall T (2009) A Wnt survival guide: from flies to human disease. J Invest Dermatol 129:1614-27 |
