Deregulated Ras signalling is observed in the vast majority of human solid neoplasias, exemplified by cutaneous melanoma. Mutational profiling suggests that activation of Raf-Mek-Erk signalling downstream of Ras may be crucial for initiating melanocyte neoplasia, whereas phosphoinositide 3-kinase (PI3K)-Akt signalling is involved in malignant progression. These hypotheses have not yet been fully tested in in vivo models. Treatment options for patients with advanced (metastatic) melanoma are very limited and their prognosis remains poor. Understanding the molecular basis of melanoma formation and progression should identify potential targets for the development of more effective medicines.
The authors generate several transgenic zebrafish melanoma models by expressing oncogenic Ras, attenuated versions of Ras, and activated Ras effectors in their melanocytes. The ability of Ras and Ras effector mutants to induce melanocyte neoplasia confirms an important role for Raf-Mek-Erk signalling in melanoma initiation. Germline transmission of oncogenic Ras produced fish that were covered with dysplastic melanocytes, which frequently progress to melanoma, reminiscent of familial atypical mole and melanoma (FAMM) syndrome seen in humans. Malignancy was abrogated in these animals by co-expressing a PI3K inhibitor, confirming a role for PI3K in melanoma progression.
The authors created and characterise zebrafish models of melanoma through disruption of Ras signalling. These fish display high penetrance and a rapid onset of melanoma. These findings and other characteristics of zebrafish, including optical clarity, forward genetic power, and amenability to transgenesis and small molecule treatment, suggest the future utility of this model in understanding and treating human cancer.