Zebrafish have been used to study heart defects, regeneration, and skin color, and melanoma, the most lethal type of human skin cancer, now can be added to that list. Last week at a meeting of the Genetics Society of America in Washington, D.C., scientists presented an update on the melanoma model, discussing how the zebrafish can be used not only to understand the genetics of skin cancer but also to test potential drugs.
In March 2011, Houvras and collaborators published an initial report in Nature describing a method to use zebrafish to screen human gene mutations for those that cause melanoma (1). They began with zebrafish carrying a mutation in the gene BRAF, known to be mutated in at least half of human melanomas and targeted by the recently approved drug vemurafenib. In fish, the mutation also leads to skin tumors. But most melanomas have other driving mutations, and vemurafenib only works transiently. So, the team wanted to see what other mutations would encourage even faster or more aggressive tumor growth in the zebrafish.
“What we’re trying to do with this approach is distinguish driver changes from passenger changes,” said Houvras. The scientists screened mutations in 35 genes from an area of the human genome known to be amplified in some melanomas. They created fish with different combinations of the genes of interest and BRAF and screened them weekly for melanomas—which stand out to the naked eye as pigmented, raised lesions on the zebrafish’s transparent skin. They found one mutation—in a gene called SETDB1, that encodes a methyl transferase enzyme—that caused melanomas to grow 50% faster and become more invasive.
Now, Houvras has turned toward understanding the function of SETDB1, which likely methylates many spots on the genome at once, broadly affecting cancer-related pathways. They’ve discovered that knocking SETDB1 out of cells causes melanocytes—a type of skin cell—to differentiate abnormally (2).
Moreover, the team is still analyzing the full genetics and epigenetics of tumors isolated from the 3000 fish in the initial experiment. And, on top of the experiments, they’re promoting their model to other scientists.
“The fish model offers a lot of opportunities in terms of chemical screens, to identify new drugs,” says Houvras. “We can continue to screen other new targets and use the same approach to screen other chromosome regions.”
- Ceol, C. J., Y. Houvras, J. Jane-Valbuena, S. Bilodeau, D. A. Orlando, V. Battisti, L. Fritsch, W. M. Lin, T. J. Hollmann, et al. 2011. The histone methyltransferase SETDB1 is recurrently amplified in melanoma and accelerates its onset. Nature 471(7339):513-517.
- “Model Organisms to Human Biology: Cancer Genetics” meeting of the Genetics Society of America presentation, June 18, 2012, Washington, D.C.