Identification of Novel Kras Effector Pathways in Lung Cancer

我们实验室的长期目标是发现治疗癌症的新分子靶点。Kras是人类癌症中最常发生突变的致癌基因之一。Kras突变在肺癌、胰腺癌和结肠癌中普遍存在。我们之前使用小鼠与人类基因表达比较来鉴定Kras突变特异性的基因表达特征。我们现在使用shRNA进行筛选，以测试该特征的功能意义，并确定潜在的转录调节因子。这个筛选已经确定了转录因子Wt1在kras驱动的肿瘤发生中的作用。在Specific Aim 1中，我们将确定Wt1与致癌Kras信号传导的联系机制。wt1是一个具有多效性的基因，既可作为肿瘤抑制基因，也可作为癌基因。我们将使用拯救实验来确定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连接Wt1和Kras效应子的关键信号通路。这些实验将通过条件Wt1敲除小鼠的可用性得到加强，该小鼠将用于我们的研究。尽管人们对癌症的分子基础有了越来越复杂的了解，但针对这些分子变化的特异性治疗仍然有限。使用复杂的功能基因组方法，我们已经确定了几个潜在的新的kras驱动的肺肿瘤发生的调节因子。在这里，我们重点剖析这两种新型调节剂的分子机制。了解Wt1在kras驱动的肿瘤发生中作用的分子基础，可能会发现适合治疗干预的新途径。

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.