The increase in skin cancer incidence in the past years has made the search for new therapeutic approaches to prevent or cure these malignancies a major research challenge. Importantly, the development of new therapies depends on a thorough understanding of the molecular mechanisms underlying the pathogenesis of these threatening disorders. The growth and differentiation factor activin A regulates a variety of processes, among them cutaneous homeostasis and repair. Most interestingly, recent results from the host laboratory revealed a pro-tumourigenic role of activin A in a mouse model of chemically-induced skin carcinogenesis, which is exerted via stromal cells, most likely the mast cells. The goal of the proposed project is to investigate the mechanisms underlying this pro-tumourigenic function of activin A. First, the contribution of mast cells to this effect will be determined. For this purpose mast cells will be depleted in activin A-overexpressing mice using a genetic approach, and the mice will be subjected to a chemical skin carcinogenesis protocol. In parallel, other stromal cell type(s), by which activin A might exert its pro-tumourigenic effect, will be identified. Moreover, the role of activin A in other tumour models will be determined by breeding the activin A-overexpressing mice to transgenic mice that develop papillomas without any physical or chemical treatment and to mice susceptible to malignant melanoma development. The study will be complemented by analysis of activin expression in human skin cancer biopsies. This analysis will allow us to define the roles and mechanisms of action of activin in the development of cutaneous tumours and may provide information on the potential use of activin antagonists or inhibitors of activin receptor signaling for the treatment of skin cancer. Knowledge gained from this study will thus not only be important for basic research, but will also be relevant for clinical practice.