Epidermal squamous cell carcinoma (SCC) represents one of the two most abundant cancers in the USA. Ras is supposed to play a major role in the development of murine and human SCC. Induction of Ras and CDK4 could be demonstrated in a subset of human SCC s. Furthermore, co-expression of Ras with CDK4 led to the induction of invasive human epidermal neoplasia indistinguishable from SCC at all stages analyzed but the underlying mechanistic basis is largely unknown. This research fellowship would enable me to study the functional role of Ras and its related components in the development of human epidermal tumorigenesis which I would like to analyze according to the following research concept: I plan to characterize the influence of three Ras effectors named Raf, PI3K and RalGEF as well as the corresponding signal transduction pathways which are known to influence cell proliferation, de-differentiation, migration or angiogenesis during tumor development. Ras mutants designed to selectively activate or inactivate one of these pathways and their effectors themselves will be used to analyze the impact of each of these pathways to Ras-driven human neoplasia. With this research concept I hope to illuminate the functional relevance of those Ras effector pathways and their extend of necessity or sufficiency for initiation of human epidermal neoplasia. The work on Ras-driven human epidermal neoplasia will expand my knowledge about the mechanistic basis of tumor development and its influence on skin homeostasis. It will help me to establish my own laboratory working on epidermal tumorigenesis when I return to Germany.
