Title: Determining Age-Dependent Metabolic Changes in Tumors and Their Microenvironment Project science areas: 6 MCB, 8 HIB Project Summary/Abstract: Aging is one of the primary risk factors for cancer and deregulated metabolism is a unifying hallmark for both aging and cancer. Yet, we do not fully understand how ageassociated metabolic changes contribute to cancer initiation and progression. Although many animal models are created to fatefully recapitulate the oncogenic events that lead to cellular transformation and cancer progression, most are carried out in young animals that likely have metabolically different tumor microenvironments and robust immune systems. To this date, few studies have systematically examined how age-dependent alterations of cellular and organismal metabolism impact tumor growth and metastasis. We hypothesize that age-associated metabolic dysregulation will significantly alter cellular metabolism both within tumor cells, as well as in cells within the tumor microenvironment, which may influence cancer progression and response to therapies. We propose a multipronged, single cell approach to characterize and resolve metabolic changes over time, both within the tumor and its microenvironment. Finally, we will assess the impact of environmental factors, such as dietary nutrients and microbiome derived metabolites, on cancer initiation and progression. Collectively, we think our findings will be transformative and will answer key questions of how aging rewires cellular metabolism and how it affects tumor growth and metastasis. We hope to elucidate important questions about cellular plasticity, metabolic heterogeneity and identify metabolic liabilities that can be accentuated by limiting specific nutrients or metabolites in new combinatorial therapies.

Project Narrative: Although both cancer rates and metabolic deregulation increase with age, it is not well understood how age-dependent metabolic changes affect cancer initiation and progression. In addition, we have limited knowledge of how age-associated metabolic differences in the tumor microenvironment contribute to carcinogenesis and how these changes are affected by environmental factors such as diet and microbial metabolites. In this proposal, we plan to elucidate age- associated metabolic changes in tumors and their microenvironment using advanced single cell technologies, which may lead to discovering metabolic liabilities and improve existing therapies.