Chemical-genetic approaches to identify novel compounds that sensitize melanocytes for cell death


Year:

Session type:

Hironori Ishizaki, Michaela Spitzer, Jan Wildenhain, Ian Jackson, Mike Tyers, Elizabeth Patton

University of Edinburgh, UK

Abstract

Chemical-genetic approaches to identify novel compounds that sensitize melanocytes for cell death

Metastatic melanoma is aggressive and resistant to all chemotherapy, with afflicted individuals having a median life expectancy of less than one year. Clues to why melanoma is so difficult to treat may come from the nature of the melanocyte itself. Derived from highly motile neural crest cells, melanoma has high metastatic potential, and armed with enhanced survival and anti-apoptotic capabilities, melanocytes are naturally resistant to cytotoxic agents. Understanding the ontogeny and biology of the melanocyte -their development from precursor/stem cells, their proliferation, migration, differentiation, interaction with their environment, and death - may be highly informative for new therapeutic approaches to melanoma. We study these processes using the zebrafish model system, which allows the visualization of melanocytes in live tissue as well as their progression tomelanoma.

Well suited to high-throughput genetic and chemical screening, zebrafish are becoming widely used in the drug-discovery process for target validation, disease modelling, toxicology and target and lead compound discovery. Screening 1600 bioactive compounds has allowed us to identify a small molecule panel that alters distinct aspects of melanocyte biology in zebrafish. One novel compound, BIO1E7 appears to specifically sensitize melanocytes for cell death by a p53-independent and tyrosinase-independent pathway. Systematic genetic profiling of 6000 yeast gene deletion mutants for compound sensitivity has enabled us to identify BIO1E7 to genetically interact with the RAD5-nucleotide excision repair pathway. We are currently testing BIO1E7 activity in mammalian melanocyte and melanoma cells, and suggest that the BIO1E7 mechanism may reveal a new point of vulnerability for melanocytes.