Characterization of Ras-driven human epidermal neoplasia

表皮鳞状细胞癌（SCC）是美国两种最常见的癌症之一。Ras被认为在小鼠和人类SCC的发展中发挥重要作用。Ras和CDK4的诱导可以在人类SCC的一个亚群中得到证实。此外，Ras与CDK4的共表达导致了侵袭性人表皮瘤变的诱导，在分析的所有阶段与SCC没有区别，但其潜在的机制基础在很大程度上是未知的。这个研究项目将使我能够研究Ras及其相关成分在人类表皮肿瘤发生发展中的功能作用，我想根据以下的研究理念进行分析：我计划描述在肿瘤发生过程中，已知的影响细胞增殖、去分化、迁移或血管生成的三种Ras效应因子Raf、PI3K和RalGEF的影响以及相应的信号转导途径。Ras突变体被设计为选择性地激活或灭活其中一种途径及其效应物本身，将用于分析每种途径对Ras驱动的人类肿瘤的影响。通过这一研究概念，我希望阐明这些Ras效应通路的功能相关性，以及它们对人类表皮肿瘤发生的必要性或充要性的扩展。ras驱动的人表皮肿瘤的研究将扩展我对肿瘤发展的机制基础及其对皮肤稳态的影响的认识。这将有助于我在回到德国后建立自己的表皮肿瘤发生实验室。

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.