Immunological and mechanical basis of spontaneous tumour necrosis and ulceration.

The presence of 'spontaneous' cancer cell death in melanoma, manifesting as ulceration at the skin surface or necrosis within deeper tissue deposits, is common and may be prognostically significant. Whether ulceration and necrosis occur by predominantly passive mechanical processes (eg: exceeding blood supply, direct trauma) or active immunological ones (eg: innate or adaptive immune cell attack) is not well understood. Pathways to ulceration or necrosis likely vary between tumour deposits, and may determine whether it is a 'good' or 'bad' prognostic feature. In this project, we will explore the immunological and tissue structural changes that occur within and adjacent to areas of ulceration and necrosis in melanoma tumours. We will use a combination of patient-derived specimens and preclinical models to perform spatial analyses of cancer cells, immune infiltrates, vasculature and extracellular structure using immunohistochemistry and digital image analyses. These data will be included in multivariable models of clinical outcome to develop refined prognostic tools, and assessed for their relationship to therapeutic outcomes as predictive biomarkers in patient cohorts. We will also evaluate the genomic and biochemical features of tumour regions adjacent to areas of cell death (necrosis) to determine what drives 'spontaneous' tumour collapse and how to exploit this process therapeutically.