Taking Human Cancer Genes to the Fish: A Transgenic Model of Melanoma in Zebrafish

MELANOMA is an aggressive, and often deadly, cancer of the skin. In one year alone in the United States, over 50,000 people are diagnosed with melanoma, from which over 7000 people die. Despite an unprecedented understanding of cancer genetics and development, the incidence of melanoma continues to rise each year and melanoma remains a disease for which few treatments are effective. Once the disease is metastatic, the average person survives less than 8 months, often enduring gruelling treatments with minimal effectiveness. Human genetic studies, coupled with Xiphophorus and mouse melanoma models, point to the activation of the RAS kinase pathway and the loss of the INK4a/ARF locus as signature genetic events in melanoma. The INK4a/ARF locus encodes two tumor-suppressors: p16INK4a that acts in the Rb-pathway to inhibit progression through G1-phase, and p14ARF that acts in the p53 pathway to inhibit p53 function. A significant recent finding by The Cancer Genome Project, The Wellcome Trust Sanger Institute, identified mutations in the BRAF kinase in 66% of melanomas. The most common mutation, V600E, is found in a remarkable 80% of cases, and causes constitutive kinase activation and mitogen activated protein kinase (MAPK) pathway stimulation. Activating BRAF mutations are also found in nevi, a nonmalignant precursor lesion, and may correlate with proliferating versus dormant nevi. Further understanding of the in vivo significance of activating BRAF mutations would require an animal model. We set out to generate a zebrafish model of BRAF to gain a deeper understanding of the gene–gene and gene–environment interactions that lead to melanoma, and ultimately identify chemical inhibitors of melanoma progression.