Clues on cancer from a zebrafish model of melanoma

Melanoma, the most lethal form of skin cancer, is an epidemic among cancers; it claims thousands of lives every year. Despite advances in cancer genetics and treatments, current therapies are only mildly effective once melanoma has become metastatic. Understanding the genetic and environmental influences that lead to melanoma will contribute to therapeutic advancement.

By studying how a particular human gene often mutated in melanoma influences melanoma development in a fish species, researchers have created a genetic model for understanding how melanoma develops humans.

An effective way to study gene function is to use an animal model, such as zebrafish, a small (3 cm) vertebrate. Within the last two decades, the zebrafish species has been used to study a wide range of diseases, in part owing to genetic similarities between humans and fish.

Past work from The Cancer Genome Project of Wellcome Trust Sanger Institute included the significant finding that the gene encoding a particular protein, BRAF kinase, is mutated in more than 65% of melanomas. Remarkably, one mutation, V600E, is found in more than 80% of cases. BRAF mutations are also found in nevi (commonly known as moles) and may represent a critical step in the initiation of melanoma development.

In the new work reported this week, Drs. Elizabeth Patton, Leonard Zon, and colleagues at Children's Hospital Boston & Harvard Medical School have advanced our understanding of the contribution of BRAF mutation to melanoma. By engineering zebrafish to express the mutated form of human BRAF in zebrafish melanocytes, the authors show that BRAF expression induces dramatic black pigmentation in the skin of the fish. Strengthening their evidence that BRAF mutation may be important for the initiation of melanoma development, the researchers found that when these fish are deficient for a cancer-protective protein called p53, they develop an aggressive melanoma. Histological analysis shows a high similarity between zebrafish and human melanomas, further strengthening the potential utility of the fish model for understanding the human disease. The zebrafish genetic model of melanoma shows that human BRAF mutations are sufficient for formation of large ectopic nevi that are highly melanoma-prone and provides a new tool for the exploration of melanoma genetics and drug development.