Melanoma is a common disease that is frequently lethal. About 50,000 new cases and 8,000 melanoma-related deaths will occur in the US in 2004. Early metastases are characteristic of melanoma and are an ominous sign, as current therapeutic interventions have little effect on survival. The lack of accurate prognostic indicators and effective therapies emphasize the need for a better understanding of the genetic and phenotypic changes in melanoma formation and progression. Activating mutations in BRAF occur in about 70% of melanomas and melanocytic nevi and implicate MAP kinase pathway signaling in melanoma. A subset of familial and sporadic melanomas have mutations involving the CDKN2A locus encoding the overlapping tumor suppressor genes p16INK4A and p14ARF. The observation that activating mutations in beta-catenin occur at a low but reproducible rate raises the possibility that constitutive WNT pathway signaling may result in melanoma. This hypothesis is supported by features of WNT pathway activation in roughly 40% of melanomas in the absence of activating beta-catenin mutations. Our goal is to evaluate the role of beta-catenin activation in benign melanocytes and on melanoma formation in mice. These studies will rely on conditional activation of beta-catenin using Cre-lox recombination and will utilize a new mouse strain expressing a tamoxifen-inducible form of Cre specifically in melanocytes that we have generated and characterized. We will utilize this mouse model to functionally evaluate the effects of melanocyte-specific activatior of beta-catenin on: 1). melanocyte proliferation, differentiation, and migration in vitro and in vivo 2). melanoma formation in conjunction with Cdnk2a loss, Pten loss or Hras activation and 3). melanoma progression to metastasis Additionally, we will determine: the relationship between melanocyte stem cells and melanoma forfnation, the replicative potential of melanocytes outside of the stem cell niche, and will examine beta-catenin signaling targets in human melanoma using a 400 sample tissue microarray.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA112054-04
Application #
7405442
Study Section
Cancer Genetics Study Section (CG)
Program Officer
Woodhouse, Elizabeth
Project Start
2005-07-01
Project End
2008-06-30
Budget Start
2008-05-01
Budget End
2008-06-30
Support Year
4
Fiscal Year
2008
Total Cost
$81,273
Indirect Cost
Name
University of Vermont & St Agric College
Department
Pathology
Type
Schools of Medicine
DUNS #
066811191
City
Burlington
State
VT
Country
United States
Zip Code
05405
Damsky, William; Micevic, Goran; Meeth, Katrina et al. (2015) mTORC1 activation blocks BrafV600E-induced growth arrest but is insufficient for melanoma formation. Cancer Cell 27:41-56
Wollmann, Guido; Davis, John N; Bosenberg, Marcus W et al. (2013) Vesicular stomatitis virus variants selectively infect and kill human melanomas but not normal melanocytes. J Virol 87:6644-59
Marsh Durban, Victoria; Deuker, Marian M; Bosenberg, Marcus W et al. (2013) Differential AKT dependency displayed by mouse models of BRAFV600E-initiated melanoma. J Clin Invest 123:5104-18
Muthusamy, Viswanathan; Premi, Sanjay; Soper, Cara et al. (2013) The hematopoietic stem cell regulatory gene latexin has tumor-suppressive properties in malignant melanoma. J Invest Dermatol 133:1827-33
Damsky, William E; Curley, David P; Santhanakrishnan, Manjula et al. (2011) ?-catenin signaling controls metastasis in Braf-activated Pten-deficient melanomas. Cancer Cell 20:741-54
Held, Matthew A; Curley, David P; Dankort, David et al. (2010) Characterization of melanoma cells capable of propagating tumors from a single cell. Cancer Res 70:388-97
Dankort, David; Curley, David P; Cartlidge, Robert A et al. (2009) Braf(V600E) cooperates with Pten loss to induce metastatic melanoma. Nat Genet 41:544-52
Yang, Guang; Curley, David; Bosenberg, Marcus W et al. (2007) Loss of xeroderma pigmentosum C (Xpc) enhances melanoma photocarcinogenesis in Ink4a-Arf-deficient mice. Cancer Res 67:5649-57
Muthusamy, Viswanathan; Hobbs, Cara; Nogueira, Cristina et al. (2006) Amplification of CDK4 and MDM2 in malignant melanoma. Genes Chromosomes Cancer 45:447-54
Cardiff, Robert D; Anver, Miriam R; Boivin, Gregory P et al. (2006) Precancer in mice: animal models used to understand, prevent, and treat human precancers. Toxicol Pathol 34:699-707

Showing the most recent 10 out of 11 publications