Gene-Environment-Microenvironment Interactions in Melanomagenesis

The overarching goal of my research program is to elucidate the molecular mechanisms of ultraviolet radiation (UVR)-induced melanomagenesis.

The major etiological risk factor for the majority of melanomas has long been known to be UVR, yet the underlying mechanisms largely remain elusive. The hunt for melanoma-initiating genes has remained focused on UVR-induced DNA mutations. However, several studies have fueled the notion that mechanisms other than direct DNA damage are also important for UVR-induced initiation and progression of melanoma. To find clues to these mechanisms, we profiled the melanocytic gene expression response to UVR exposure while in their normal skin microenvironment (Nature 469:548). To circumvent the considerable challenge of studying a cell type in vivo that constitutes a tiny fraction of the mammalian skin, we developed a mouse model in which melanocytes can be both imaged in vivo and highly purified by virtue of tetracycline-inducible, melanocyte-specific GFP expression (iDct-GFP mice). This novel mouse model provides an invaluable tool to explore melanocyte and melanoma biology while residing within their natural microenvironment.

We have shown that the role of UVR in melanomagenesis involves not only UVR-induced DNA damage, but also how altered gene expression in exposed melanocytes drives interactions with elements of the microenvironment to escape destruction. Our results suggest that UV insult stimulates an intricate interplay between melanocytes and the skin microenvironment. It is clear that the alterations in melanocytic gene expression profile following UVR exposure stem from a combination of the direct UVR-induced effects on melanocytes and microenvironmental cues. We intend to tease out these intrinsic and extrinsic mechanisms to delineate the important molecular players in UVR-induced melanomagenesis.