Tumor progression in a mouse model of lung cancer

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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.