Fane, M.E.2 , M.2, Lim, W.1, Sturm, R.1 and Smith, A.G.1,2,*
1Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia
2School of Biomedical Sciences, The University of Queensland, Brisbane, Australia
Metastatic melanoma is a complex and heterogeneous disease, which is highly resistant to conventional chemotherapies and radiation. Recent development of small molecular weight inhibitors for the mutant BRAF kinase (present in approximately 50% of melanomas), induce dramatic tumour regression in many patients, however tumour resistance to these agents develops in the majority of patients within 6 to 12 months. Accordingly, a deeper understanding of the cellular programs that underpin melanoma growth, invasion and metastasis is required to identify novel targets to treat this disease. The transition from radial to vertical growth phase is a pivotal event associated with the metastatic transformation of melanoma cells. The basis of the molecular switch that occurs and confers the ability of tumour cells to migrate is unknown, however accumulating evidence suggests that these cells undergo epigenetic changes driven by specific expression programmes imposed by the cellular microenvironment that allows switching between a proliferative or invasive phenotype. Recent findings have now shown that both in vitro and in vivo models of metastatic melanoma contain two distinct subpopulations characterised by an inverse expression profile between the MITF and BRN2 transcription factors. While BRN2 has clearly been shown to play a role in increasing invasiveness and tumorigenicity of tumour cell populations, there is very little known about downstream signalling targets that BRN2 regulates to allow such a phenotype. Using both BRN2 gain and loss of function models in-vitro, we have found that BRN2 regulates NOTCH, IRF4, and NFIB signalling, all of which may play a role in increasing the migratory and tumorigenic potential of these BRN2 expressing populations. We have also developed a genetic model of invasive melanoma in zebra fish using transient melanocyte specific expression of oncogenic H-RAS in which nodular tumours are only seen in combination with BRN2 over-expression. Using an enhancer trap Gal4-UAS system, we hope to replicate this phenotype using stable transfection of both H-RAS and BRN2 and study the histological and metastatic features of these tumours throughout development.