PROJECT SUMMARY Non-Small Cell Lung Cancer (NSCLC) remains the highest mortality cancer in the United States, with approximately 70% of patients not eligible for curative surgical resection at diagnosis. Thus, the advent of novel systemic therapeutics, especially those which are efficacious for metastatic disease, is of primary importance. A functional genomic screen conducted in our laboratory identified the H3K36 demethylase KDM2A as a regulator of KRAS/P53 mutant NSCLC metastasis. KDM2A is known to also have roles in DNA damage repair, thus I hypothesize that KDM2A is important to preserving the genomic stability of NSCLC cells by mediating genotoxic stress, and to metastasis by controlling transcriptional responses to the tumor microenvironment. The primary aims of this project are to elucidate the molecular mechanism by which KDM2A promotes NSCLC proliferation/survival, and to determine the steps of the metastatic cascade for which KDM2A is important. To answer these questions I will leverage bioinformatic analysis, functional mutants, and animal models. In Aim 1, I will use functional mutants of KDM2A to assay importance of each functional domain to proliferation and survival, as well as assaying the impact of KDM2A loss on markers of genomic stress. In Aim 2, I will use in vivo models of metastasis to examine the molecular functions of KDM2A that are important to various steps of the metastatic cascade, as well as using a variety of injection and assay techniques to pinpoint the step(s) of the cascade at which KDM2A is important. The completion of this project will reveal the molecular mechanism of a novel potential clinical target of advanced NSCLC. My project is easily translatable to clinical research, as a research grade chemical inhibitor of KDM2A exists and could be optimized for clinical deployment.