Dissecting cellular hierarchies in normal and neoplastic melanocytic development

Background. Melanoma is the most common cancer in young Australians. In part because of this, melanoma has the second-most detrimental socioeconomic impact of all cancers in Australia. Although recent advances in understanding oncogenic drivers and tumor-host immune interactions in melanoma have revolutionised the systemic treatment of advanced disease, with remarkable benefits for some patients, understanding of how melanomas actually form from normal melanocytes remains rudimentary. Mainly, this is because relatively little is known about how normal melanocytes in the skin and other tissues are organised and maintained, including in the face of environmental carcinogens such as ultraviolet light. To address this, our laboratory has developed novel assays to enable prospective isolation and functional testing of normal melanocytes from mice or humans. These studies have revealed phenotypic and functional heterogeneity amongst melanocytes that indicates hierarchical relationships between progenitor and differentiated melanocytes, consistent with structures described for other organ systems. These observations open the way for detailed evaluation of mechanisms that drive proliferation, self-renewal, differentiation and neoplastic change in melanocytes. Aims. Project aims will depend on the degree sought, but potentially include: 1) Identification and functional characterization melanocyte subpopulations from mouse and human skin 2) Identification and validation of molecular differences between functionally distinct melanocytes 3) Identification of changes in functional behaviours and molecular signaling in melanocyte subpopulations during their malignant transformation Methods/Techniques. The project will avail patient tissues, mouse models, flow cytometry, cell and molecular biology techniques, molecular profiling and informatics approaches to interrogate melanocyte biology and malignant transformation in unprecedented detail. Key references. Nature 545:175, Nature 456:593, Nature 439:993, Nature 439:84, Nat Cell Biol 9:201, J Natl Cancer Inst 98:1011, Nat Med 18:1239, Nat Biotech 4:1010, Cancer Research 68:7711, Cancer Research 76:3965