In another application of this line, BRAF expression was associated with a distinct gene signature that resembled expression profiles of embryonic neural crest stem/progenitor cells, thereby motivating White

et al. [ 30••] to screen for suppressors of this embryonic phenotype. A class of compounds, called inhibitors of dihydroorotate dehydrogenase (DHODH), was found to selectively abrogate neural crest development in zebrafish as well as melanoma growth in mouse xenografts and human cell lines. Currently being followed in Phase I/II clinical trials, the DHODH inhibitor leflunomide is a pivotal demonstration of how an embryonic phenotype can be translated to findings about Trametinib in vitro the human disease and lead molecules from zebrafish research into clinical investigation. Detailed live imaging of melanocytes in a temperature sensitive mitfa (mitfavc7) mutant has provided novel insights into the direct consequences of mitfa activity on tumorigenesis. Reduced mitfa activity caused a dramatic increase in melanocyte ERK high throughput screening cell division [ 31] and was found to directly affect tumor morphology and formation in the BRAF model [ 32•]. As these findings could be reversed with the restoration of mitfa’s

activity, this work substantiates the notion that mitfa is a modifier of BRAF-driven melanoma and provides a functional link between low MITF expression in patients with their poor melanoma prognosis. Recent studies using a KRASG12D-driven model of embryonal rhabdomyosarcoma (ERMS) [ 11] have highlighted the importance of the cell of origin as a determinant of ERMS. For example, Ignatius et al. [ 33] used dynamic cellular imaging of a mosaic transgenic rag2-KRASG12D model to track the movement and evolution of ERMS cell subpopulations in embryonic and adult zebrafish. Their findings revealed new roles for differentiated ERMS cells in tumor growth and suggest that mechanisms governing their homeostatic maintenance in regulating growth could be relevant considerations

in developing Avelestat (AZD9668) potential therapeutic treatment. In a similar approach, using promoters representing various stages of muscle development (cdh15, rag2, mylz2), Storer et al. [ 34] drove expression of KRASG12D and observed that tumors that originated from the more progenitor like cells were more invasive and undifferentiated. These tumors were found to closely recapitulate subgroups of human ERMS based on differentiation status and harbor unique signaling pathways in each subgroup. Confirmation of these pathways as therapeutic targets awaits further study but demonstrates how cross-species oncogenomics can be used to guide therapeutic targeting strategies. Important insights have also been described in other zebrafish models that cannot be described here [35, 36, 37, 38 and 39] (reviewed in [40••, 41••, 42 and 43]). It is apparent though that some tumor types are better modeled in zebrafish than others.