My research projects investigate the pathogenesis and treatment of melanoma, and in part are directed at developing tools to study melanoma.
Objective One: The development of mouse models of melanoma.
I am developing mouse models of melanoma that mimic different stages of human disease clinically, pathologically and genetically. Experiments are evaluating new immunotherapies at different stages of tumor progression. My hypothesis is that mechanisms of immunity against premalignant lesions (e.g., dysplastic nevi), primary melanoma and metastatic melanoma are distinct. We are creating crosses between transgenic mouse lines expressing mutated Braf, glutamate metatropic receptor 1 and NRAS and deficiencies in INK4a and Pten, all genes implicated in the pathogenesis of melanoma. Currently, our mouse strains range from premalignant melanocytic lesions to metastatic melanoma. For future studies, we are developing inducible, conditional, tissue-specific mouse melanoma models with epidermal melanocytes, which should more accurately mimic the human disease. Long-term I would like to use these mouse models to screen genetic modifiers, potentially identifying novel genes involved in melanoma pathogenesis and discovering new candidates for therapeutic targets.
Objective Two: Examining the interaction between tumors and the immune system.
We are generating mice whose immune cells are genetically labeled with fluorescent proteins. These mice will allow us and others to track the in vivo behavior of specific immune cells (melanoma/melanocyte-specific CD4 T cells, melanoma/melanocyte-specific CD8 T cells, regulatory T cells, dendritic cells and other myeloid cells) in a melanoma-bearing host. We utilize combined multiphoton/confocal intravital imaging of mouse skin to characterize cellular interactions over space and time between tumor cells and the immune system, in collaboration with the Research Engineering Core.
Objective Three: Role of FAP (fibroblast activation protein-alpha) in tumorigenesis.
FAP is a cell surface protease expressed only at sites of tissue remodeling and wound healing but not by adult somatic cells. The Houghton lab has observed complete loss of FAP expression when cutaneous melanocytes transform into melanoma cells and has shown that FAP controls cell growth and proliferation of melanocytic cells. We are studying tumorigenesis in FAP deficient mice, observing that deficient mice are more susceptible to carcinogen-induced tumor development than FAP heterozygous or wild type littermates. My aim is to determine the mechanisms by which FAP protects against tumor formation using genetic approaches with melanoma-prone mice developed in our lab, examining different pathways for regulation of cell growth, including ras-Braf-mek, INK4a, p53 and Pten/Akt.