Marcus Bosenberg, MD, PhD, assistant professor of pathology, recently was awarded $1.35 million over a five-year period in the form of an R01 grant from the National Institutes of Health / National Cancer Institute. The award will fund a project to examine the effect of beta-catenin signaling activation on melanocyte function and melanoma formation. The project experiments will involve a new mouse model of melanoma, created by Bosenberg and his colleagues, as well as the construction and analysis of a tissue microarray to evaluate beta-catenin signaling in human melanoma.
"Malignant melanoma is the most deadly form of skin cancer," says Bosenberg. "At present, only a few genes which, when altered, are known to increase the chances of getting melanoma. Beta-catenin is an additional candidate gene that is mutated in about 5% of melanomas, but may be active in up to 40% of melanomas. We will functionally evaluate whether beta-catenin activation leads to melanoma formation and metastasis. The answer to these questions may speed up the process of initiating clinical trials with novel small molecule inhibitors of beta-catenin in melanoma patients. The grant will also allow us to create a tissue microarray of melanoma samples to evaluate whether beta-catenin signaling is altered in human melanoma or correlates with better patient prognosis."
Malignant melanoma is a common disease that is frequently lethal. About 50,000 new cases and 8,000 melanoma-related deaths occurred in the U.S. in 2004. Early metastases are characteristic of melanoma and are an ominous sign, as current therapeutic interventions have little influence on survival. Histopathological criteria remain the primary factors used to predict patient prognosis, with tumor thickness and sentinel lymph node status being the most reliable parameters. However, for tumors greater than one millimeter in thickness, the ability to accurately predict patient prognosis is generally poor. Although recent progress has been made, little is known about the specific genetic changes responsible for melanoma formation and progression. Activating mutations in the BRAF gene occur in about 70% of melanomas and melanocytic nevi, implicating MAP kinase signaling in melanoma. A subset of familial and sporadic melanomas have mutations involving the CDKN2A locus at 9p21 that encodes the overlapping tumor suppressor genes p16INK4A and p14ARF. Cytogenetic and comparative genomic hybridization experiments have demonstrated several additional recurrent chromosomal changes that likely target additional melanoma oncogenes or tumor suppressors. 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.
The observation that activating mutations in beta-catenin occur in melanoma at a low but reproducible rate raises the possibility that constitutive WNT pathway signaling may result in melanoma. This hypothesis is supported by the finding of features of WNT pathway activation in roughly one-third of melanomas and the demonstration that beta-catenin is required for the survival and differentiation of neural crest-derived melanocyte precursors.
Bosenberg's studies will utilize conditional Cre-lox recombination in mice with a novel mouse strain that his laboratory has generated and characterized, and that expresses a tamoxifen-inducible form of Cre specifically in melanocytes. This strain will be used in conjunction with a mouse strain that has a conditionally activatable form of beta-catenin. Bosenberg will utilize this mouse model to functionally evaluate the effects of somatic activation of beta-catenin in melanocytes and on the formation and progression of malignant melanoma. Using this new melanoma model, Bosenberg will also evaluate the role of melanocytic stem cells in melanoma formation and will evaluate beta-catenin targets as potential prognostic and diagnostic markers using melanocytic tissue microarrays.