Tumor Macroenvironment and the Circadian Metabolic Clock

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Project Summary/Abstract Cancer cells exhibit a heightened metabolic demand that is satisfied by an increased rate of aerobic glycolysis, termed the Warburg effect. Yet, this metabolic demand of cancer cells also results in metabolic ‘waste’ by-products that are secreted systemically. As an example, the glycolytic by-product lactate is reported to be involved in metabolic reprogramming of adjacent tissues and can induce a pro-inflammatory response. Similarly, tumor-derived pro-inflammatory cytokines have been reported to alter functions of metabolic tissues such as liver, fat and the pancreas. We hypothesize that these tumor-dependent metabolic waste by-products and inflammatory cytokines, the so-called tumor ‘macroenvironment,’ can distally reprogram the functions of the circadian metabolic clocks in the liver and pancreas. Using a lung adenocarcinoma mouse model, we hypothesize that the tumor macroenvironment inhibits clock-controlled insulin secretion in lung tumor-bearing (TB) mice, resulting in an enhanced rate of hepatic gluconeogenesis. We aim to provide the molecular mechanism for the changes in clock- controlled hepatic glucose production. Moreover, we propose that this enhanced hepatic glucose production could feedback and satisfy the metabolic demand of the tumor, and experiments will be performed to address this. We also hypothesize that the inflammatory response is targeting pancreatic islet function, subsequently resulting in inhibition of insulin production or secretion. We propose a metabolic profiling of the serum over the circadian cycle to determine in an unbiased manner what tumor- dependent metabolites could be mediating this crosstalk with peripheral metabolic clocks, such as liver and pancreas. Overall, we hypothesize that the tumor macroenvironment could play an important role in reprogramming circadian metabolic functions of the liver and pancreas. This work has important clinical implications for potential novel systemic therapeutic strategies to treat cancer.