Identification of Novel Kras Effector Pathways in Lung Cancer

我们实验室的长期目标是确定癌症的新分子靶点。Kras是人类肿瘤中最常发生突变的癌基因之一。Kras突变在肺癌、胰腺癌和结肠癌中普遍存在。我们先前使用小鼠与人的基因表达比较来鉴定Kras突变特异性的基因表达特征。我们现在已经使用shRNA进行了筛选，以测试该签名的功能意义，并确定潜在的转录调节因子。该筛选确定了转录因子Wt1在Kras驱动的肿瘤发生中的作用。在具体目标1中，我们将确定Wt1与致癌Kras信号传导的联系机制。Wt1基因是一个具有多效作用的基因，同时具有抑癌基因和癌基因的双重作用。我们将使用救援实验来定义Wt1亚型在Kras诱导的肿瘤发生中的作用。此外，我们概述了几种方法来确定的关键信号通路，连接Wt1 Kras效应。这些实验将通过将用于我们研究的条件性Wt1敲除小鼠的可用性得到加强。尽管对癌症的分子基础的理解越来越复杂，但针对这些分子变化的特定疗法仍然有限。使用复杂的功能基因组学方法，我们已经确定了几个潜在的新的调节Kras驱动的肿瘤发生在肺。在这里，我们专注于解剖这些新的监管机构的分子机制。理解Wt1在Kras驱动的肿瘤发生中的作用的分子基础可能会发现新的途径，这些途径将适用于治疗干预。

The long-term objective of our laboratory is to identify novel molecular targets for cancer. Kras is one of the most frequently mutated oncogenes in human cancer. Kras mutations are prevalent in lung, pancreas and colon carcinomas. We previously used mouse-to-human gene expression comparisons to identify a gene expression signature specific to Kras mutation. We have now carried out a screen using shRNA to test the functional significance of this signature and identify potential transcriptional regulators. This screen has identified a role for the transcription factor Wt1 in Kras-driven oncogenesis. In Specific Aim 1 we will identify the mechanism linking Wt1 to oncogenic Kras signaling. Wt1is a gene with pleiotropic effects involving roles as both a tumor suppressor and oncogene. We will use rescue experiments to define the role of Wt1 isoforms in Kras-induced oncogenesis. In addition, we outline several approaches to identify the key signaling pathways that link Wt1 to Kras effectors. These experiments will be strengthened by the availability of a conditional Wt1 knock-out mouse that will be used in our studies. Despite an increasingly sophisticated understanding about the molecular underpinnings of cancer, specific therapies that target these molecular changes are limited. Using sophisticated functional genomic approaches, we have identified several potential novel regulators of Kras-driven oncogenesis in the lung. Here we focus on dissecting the molecular mechanisms of two of these novel regulators. An understanding of the molecular basis for a role of Wt1 in Kras-driven oncogenesis may identify novel pathways that would be amenable to therapeutic intervention.