Infection, Immunology and Translational Medicine - 'Establishment of a transgenic zebrafish model to study the innate immune response to melanoma' (360G-Wellcome-097111_Z_11_Z)

Although immune mechanisms, such as cytokines produced by immune cells in response to the tumour environment, may provide protection against cancer by elimination of transformed cells, they may also aid tumour development by immunosuppressive mechanisms. Epigenetic mechanisms that alter chromatin landscape, enabling the unwrapping of transcriptional programs play important roles in all cellular processes including immune response mechanisms and carcinogenesis. It remains difficult to assess the overall effect of innate immunity during early tumourigenesis since direct in vivo models for evaluating the effects ofthese phenomena on initial tumour growth are missing. We propose to develop a melanoma model in zebrafish to study the initial host immune response to melanoma with particular focus on epigenetic changes. Key Goals 3.1 Establish a zebrafish model system to study the innate immune response to melanoma. 3.2 Characterise the interaction of neutrophils and macrophages with oncogenicmelanocytes as compared to normal melanocytes in vivo. 3.3 Carry out a genome-wide analysis of macrophages and neutrophils' response to melanoma compared to control melanocytes. i. Identify differentially expressed genes by comparing transcriptomes of innate immune cells ii. Identify changes at the epigenomic level in innate immune cells that may be resulting in differential cytokine expression 3.4 Investigate findings in melanoma patients.