Abstract

BackgroundMelanoma 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.Methodology and Principal FindingsUsing 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 and SignificanceThis 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.

Highlights

  • Melanoma development has classically been described as a stepwise process in which mature melanocytes acquire increasing number of mutations in oncogenes or tumor suppressor genes leading to uncontrolled proliferation, acquisition of invasive properties and metastatic potential [1]

  • 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

  • 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

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Summary

Introduction

Melanoma development has classically been described as a stepwise process in which mature melanocytes acquire increasing number of mutations in oncogenes or tumor suppressor genes leading to uncontrolled proliferation, acquisition of invasive properties and metastatic potential [1]. The progression from benign nevi, radial growth, vertical growth and metastatic melanomas is not a universal feature of all melanomas, with more than 50% of the tumors originating from normal skin, rather than from dysplastic nevi [2]. This data suggest that melanoma appears to be due to the transformation of mature melanocytes, it may derive from melanocytic progenitor or stem cells that upon transformation become able to initiate and maintain cancer development. 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

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