Progenitor cell states contributing to aging and lung cancer Abstract Lung cancer is the single largest contributor to global cancer mortality. With the exception of smoking, age is the single biggest risk factor for all major lung diseases, including cancer, highlighting the role of age-associated changes in the lung for mortality. Metabolic changes and epigenetic alterations are both hallmarks of aging, but little is known about how aging specifically impacts the lung and in particular lung progenitor cells. Furthermore, the synergy between metabolism and epigenetic states is emerging as an exciting new field for which implications in disease including cancer are only beginning to be explored. Preliminary data we have collected suggest that both metabolic and epigenetic changes accompany aging in lung alveolar type II (AT2) cells, the primary cell-of- origin of the most common form of lung cancer, lung adenocarcinoma. Our study will test the hypothesis that alterations in metabolic pathways driven by epigenetic changes in AT2 cells contribute to increased tumor initiation during aging. Firstly, we will map metabolic and epigenetic changes in aged AT2 cells using state of the art technologies that will enable resolution of these differences onto highly select populations and even single cells. Furthermore, we will create new models to study the effects of aging in cancer. New organoid models of lung cancer initiation will be developed to support rapid modeling of the cellular and molecular aspects of cancer in aged cells. Genetically engineered mouse models will be derived to model tumorigenesis in the aging lung. Finally, we will probe the specific mechanism by which loss of epigenetic modifications, mediated by the methyltransferase G9a, during aging contributes to increased tumor initiation through dysregulation of metabolic genes and the metabolome. These studies will combine the strengths of two experienced PIs with expertise in aging, metabolism, stem cell biology and cancer to generate new models of lung cancer and provide significant insight into the synergy of two major hallmarks of aging in the most-deadly form of cancer.

Progenitor cell states contributing to aging and lung cancer Narrative Aging is a primary risk factor for lung cancer, which accounts for the largest cause of cancer deaths. Cells in the lung alveoli are the source of the most common lung cancers and slowly become less functional as they age. We will use new models to investigate how molecular changes in alveolar cells contribute to cancer initiation during aging.