Tumor progression in a mouse model of lung cancer

描述（由申请人提供）： 我们的实验室已经开发了一种小鼠模型的人肺癌，其中激活的突变Kras基因是启动致瘤事件。 这些小鼠发展出组织学上与人类肺腺癌相似的肺肿瘤。 这些小鼠中的肿瘤显示出组织学进展的明确证据。 鉴于Kras突变在人类肺癌中很常见，该模型提供了一个独特的机会来分析重要人类疾病模型中的肿瘤进展。 虽然已经广泛研究了过表达的突变Ras在体外对人和鼠成纤维细胞的影响，但关于单拷贝突变Ras在体内对上皮细胞的作用知之甚少。 此外，关于可能与Ras突变合作以组织特异性方式促进肿瘤生长和化疗抗性的次级遗传改变或表观遗传途径知之甚少。 用于高通量全基因组分析的新技术现在使得识别与癌症进展相关的特定分子谱成为可能。 我们建议将联合收割机在DNA水平上的变化分析与该模型中肿瘤中基因表达的分析相结合，作为发现肿瘤进展中重要的新途径的策略。 此外，我们建议分析这些小鼠体内肺肿瘤的DNA损伤反应，作为开始解剖细胞自主和非细胞自主调节剂对化疗药物的反应的策略。

DESCRIPTION (provided by applicant): Our laboratory has developed a mouse model of human lung cancer in which activation of a mutant Kras gene is the initiating tumorigenic event. These mice develop lung tumors histologically similar to human lung adenocarcinoma. The tumors in these mice demonstrate clear evidence of histological progression. Given that Kras mutation is common in human lung cancer, this model provides a unique opportunity to analyze tumor progression in a model for an important human disease. While the effects of over-expressed mutated Ras on human and murine fibroblasts in vitro has been extensively studied, much less is known about the role of a single-copy mutated Ras on epithelial cells in vivo. In addition, little is known about secondary genetic alterations or epigenetic pathways that may cooperate with a Ras mutation to promote tumor growth and chemotherapy resistance in a tissue-specific manner. New techniques for high-throughput genome-wide analysis now make it feasible to identify specific molecular profiles associated with progression of cancer. We propose to combine the analysis of changes at the DNA level with analysis of gene expression in tumors from this model as a strategy for the discovery of novel pathways important in tumor progression. In addition, we propose to analyze the in vivo DNA damage response of lung tumors in these mice as a strategy to begin to dissect cell-autonomous and non cell-autonomous modulators of the response to chemotherapeutic agents.