University of Kentucky

Welcome to the D'Orazio Lab at the University of Kentucky!

The D'Orazio Research Team. Pictured (from left to right) are John, Maddy, Robert, Stuart, Kati and Nathaniel, September 2017.

Our laboratory focuses on malignant melanoma of the skin, a cancer that kills more than 10,000 Americans every year. Melanoma incidence has increased so much over the last century such that whereas a US citizen in the 1930's had only a 1 in 1,500 chance of developing it, now almost 1 in 50 of us will be diagnosed with the disease. We are interested in the genetic and environmental factors that cause melanomas to develop so that we can design ways to reduce melanoma incidence.

Our lab at the University of Kentucky's NCI-designated Markey Cancer Center focuses on the basic cellular mechanisms that influence whether melanocytes in the skin will develop into melanoma. Since UV radiation in the form of sunlight or artificial tanning lamps is a major causative risk factor for melanoma, we explore how melanocytes cope with UV exposure.

Malignant melanoma of the skin is the deadliest skin cancer. Its incidence has been increasing for decades in the U.S. and other nations. We are working to understand how melanoma develops in order to develop useful preventive strategies.

Our focus is on the melanocortin signaling axis since this pathway plays a major role in resistance to UV damage and protects melanocytes from malignant conversion into melanoma. This pathway involves secreted factors from keratinocytes - the melanocortins alpha-melanocyte stimulating hormone (α-MSH) and adrenocorticotrophic hormone (ACTH). Each functions as a high-affinity ligand for the melanocortin 1 receptor (MC1R), a cell surface protein on melanocytes that regulates several critical UV responses. When MC1R binds melanocortins, it activates an intracellular signaling cascade mediated by the second messenger cAMP. Increases in cAMP result in melanocytes being better protected from UV injury by boosting melanin production, by increasing resistance to oxidative damage and by improving the efficiency of DNA repair. Projects in the lab range from understanding how MC1R signaling is regulated to discovering how it protects melanocytes against mutagenesis.

People with inherited defects in MSH-MC1R signaling are up to 4 times more likely to develop melanoma, illustrating its importance in melanoma resistance. Millions of Americans harbor loss-of-function signaling mutations in MC1R, making them sun-sensitive, melanoma-prone and in need of the "smart" UV protective strategies that we are in the process of designing. Our long-term goal is to develop translational UV-protective strategies based on a detailed understanding of the melanocortin signaling axis and melanocyte genomic stability.