As our understanding of disease translates from basic science to clinical application there is a need for robust preclinical models to test interventions and therapies, which mirror the clinical situation and likely outcomes. This will assist key stage decision making before costly clinical trials are commenced. Skin diseases represent a significant health burden. Non-melanoma skin cancers including basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are the most common human malignancies. Genetic skin diseases, or genodermatoses, are heritable conditions comprising nearly 300 distinct often rare clinical entities, which affect ~30M people in Europe i.e. ~7% of the entire population (http://geneskin.idi.it/homepgs/rareg.php). Thus, genodermatoses have important medical and social implications and have very limited therapeutic possibilities. This proposal will develop preclinical models which can be used to identify therapeutic targets for the treatment of skin cancer and to explore novel approaches to gene and cell therapy. Organotypical tissue engineered skin constructs combining normal, malignant and diseased epithelial, mesenchymal and connective tissue elements will first be used to examine the effect of tumour microenvironment on cancer cell invasion. Then constructs mimicking 1. intraepithelial, 2. well and 3. poorly differentiated SCCs will be used as surface xenotransplants. Optimisation will examine the contribution of adipocyte and mesenchymal stem cells. A set of genes identified as a characteristic SCC signature by extensive previous studies will then be genetically manipulated to examine the effects of up and down regulation of these genes in tumour progression and invasion. The effects of novel small molecules will also be tested. Surface xenotransplants of organotypical cultures of genetically diseased keratinocytes will be established to assess the long term outcomes of comparing ex vivo gene therapy with protein and cell therapy.