Tumor progression in a mouse model of lung cancer

描述（由申请人提供）：我们实验室开发了一种人类肺癌小鼠模型，其中Kras突变基因的激活是初始致瘤事件。这些小鼠的肺肿瘤在组织学上与人类肺腺癌相似。这些小鼠的肿瘤表现出组织学进展的明显证据。鉴于Kras突变在人类肺癌中很常见，该模型为分析一种重要人类疾病的模型中的肿瘤进展提供了独特的机会。虽然体外过度表达的突变Ras对人和小鼠成纤维细胞的影响已经被广泛研究，但对于体内单拷贝突变Ras对上皮细胞的作用知之甚少。此外，关于继发性遗传改变或表观遗传途径可能与Ras突变合作以组织特异性方式促进肿瘤生长和化疗耐药，我们知之甚少。高通量全基因组分析的新技术现在使鉴定与癌症进展相关的特定分子谱成为可能。我们建议将DNA水平的变化分析与肿瘤中基因表达的分析结合起来，作为发现肿瘤进展中重要的新途径的一种策略。此外，我们建议分析这些小鼠肺肿瘤的体内DNA损伤反应，作为开始解剖对化疗药物反应的细胞自主和非细胞自主调节剂的策略。

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.