title: Kita driven expression of oncogenic HRAS leads to early onset and highly penetrant melanoma in zebrafish.
abstract: BACKGROUND
  Melanoma is the most aggressive and lethal form of skin cancer. Because of the increasing incidence and high lethality of melanoma, animal models for continuously observing melanoma formation and progression as well as for testing pharmacological agents are needed.
  
  
  RESULTS
  Using the combinatorial Gal4-UAS system, we have developed a zebrafish transgenic line that expresses oncogenic HRAS under the kita promoter. Already at 3 days transgenic kita-GFP-RAS larvae show a hyper-pigmentation phenotype as earliest evidence of abnormal melanocyte growth. By 2-4 weeks, masses of transformed melanocytes form in the tail stalk of the majority of kita-GFP-RAS transgenic fish. The adult tumors evident between 1-3 months of age faithfully reproduce the immunological, histological and molecular phenotypes of human melanoma, but on a condensed time-line. Furthermore, they show transplantability, dependence on mitfa expression and do not require additional mutations in tumor suppressors. In contrast to kita expressing melanocyte progenitors that efficiently develop melanoma, mitfa expressing progenitors in a second Gal4-driver line were 4 times less efficient in developing melanoma during the three months observation period.
  
  
  CONCLUSIONS
  This indicates that zebrafish kita promoter is a powerful tool for driving oncogene expression in the right cells and at the right level to induce early onset melanoma in the presence of tumor suppressors. Thus our zebrafish model provides a link between kita expressing melanocyte progenitors and melanoma and offers the advantage of a larval phenotype suitable for large scale drug and genetic modifier screens.
authors.affiliation: IFOM Foundation-FIRC Institute of Molecular Oncology, Milan, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Santoriello
authors.forename: Elisa
authors.initials: E
authors.lastname: Gennaro
authors.forename: Viviana
authors.initials: V
authors.lastname: Anelli
authors.forename: Martin
authors.initials: M
authors.lastname: Distel
authors.forename: Amanda
authors.initials: A
authors.lastname: Kelly
authors.forename: Reinhard W
authors.initials: RW
authors.lastname: Köster
authors.forename: Adam
authors.initials: A
authors.lastname: Hurlstone
authors.forename: Marina
authors.initials: M
authors.lastname: Mione
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D004195:Disease Models, Animal; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D016158:Genes, p53; D008544:Melanocytes / Q000166:cytology / Q000378:metabolism; D008545:Melanoma / Q000235:genetics / Q000378:metabolism*; D008957:Models, Genetic; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D010641:Phenotype; D011401:Promoter Regions, Genetic; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism*; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism*; D019076:Transgenes; D015027:Zebrafish
chemical_list: D019009:Proto-Oncogene Proteins c-kit; D051059:PTEN Phosphohydrolase; D016283:Proto-Oncogene Proteins p21(ras)