Project Summary/Abstract Lung adenocarcinoma is a complex disease with high prevalence and mortality. The low survival rate is worsened by the long-term ineffectiveness of many cancer therapeutics, which eliminate most but not all of the cancer cells in a tumor. Cellular phenotypic diversity is an important feature of cancer for the fields of basic biology and medicine, but the mechanisms by which tumors establish and maintain this diversity is poorly understood. One key aspect of tumor phenotypic diversity is proliferative heterogeneity: the presence of cancer cells that exist in proliferative states ranging from quiescence to persistent cell division. The Wnt pathway is a potentially important driver of proliferative heterogeneity, as it is central to the maintenance of a highly proliferative, cancer stem cell- like state in lung adenocarcinoma. To interrogate proliferative heterogeneity in an unbiased manner, we have established a novel genetically engineered mouse model of lung adenocarcinoma that enable us to identify different tumor subpopulations based on proliferative state. We will use this mouse model to isolate highly proliferative and persistently quiescent cancer cells, which we will then interrogate functionally and transcriptionally. In these experiments we seek to identify the impact of a cell?s proliferative state on its tumorigenic capacity (Aim 1). We will also characterize the mechanisms by which distinct proliferative states are established and maintained. In particular, we will focus on the Wnt pathway to identify the role of individual Wnt ligands in driving distinct proliferative states. The goal of these experiments is to determine the impact of targeting Wnt signaling on specific proliferative states and to identify additional cell states with robust growth potential (Aim 2). Lung cancer has a poor prognosis, but basic science research that improves the understanding of lung tumor heterogeneity can lead to significant advancements in how patients are treated. Further elucidating the phenotypic diversity that causes disease relapses may advance our ability to control tumor behavior and increase the ability of existing cancer treatments to fully eradicate the disease through elimination of resistant cell states.