Abstract 2467: Adiponectin receptor agonism induces a metabolic switch in pancreatic cancer cells from oxidative phosphorylation to glycolysis

Understanding the impact of risk factors on the progression of pancreatic cancer is critical for the development of novel therapeutics. Multiple studies have clearly shown that obesity positively correlates with increased progression of pancreatic adenocarcinoma (PDAC). We have demonstrated that individual adipose derived cytokines (aka adipokines) can elicit either pro-tumorigenic or anti-tumorigenic effects on PDAC progression. We previously demonstrated that adiponectin receptor agonism effectively suppresses pancreatic cancer growth in vitro as well as in vivo, through suppression of MAPK as well as STAT3 pathways. Yet, adiponectin is well known to stimulate the AMPK pathway and therefore we hypothesized that adiponectin agonism could also be affecting metabolic function in PDAC. In our current studies, we defined multiple metabolic alterations in pancreatic cancer cells in response to adiponectin receptor agonism using a seahorse-based assay. Human and murine PDAC cell lines were seeded into XFe96 microplates and subjected to a mitochondrial stress test as well as the glycolysis stress test. Our results demonstrate that adiponectin receptor activation impairs pancreatic cancer mitochondrial function leading to a metabolic switch from mitochondrial respiration to glycolysis. We further demonstrate that this switch is associated with AMPK phosphorylation-mediated inhibition of Acetyl Coenzyme A Carboxylase (ACC), the lipogenic enzyme whose inhibition induces fatty acid breakdown. Thus, our results support a role for adipose-secreted factors to influence the metabolic phenotype of pancreatic cancer. Since metabolic rewiring is often associated with development of chemotherapeutic resistance in cancer, we are currently testing whether dual therapeutic targeting of the mitochondrial respiration, via adiponectin receptor agonism, and glycolysis would provide an efficacious therapeutic. Citation Format: Sharon J. Manley, Jarrid Jack, Joseph Ambrose, Appolinaire A. Olou, Michael N. VanSaun. Adiponectin receptor agonism induces a metabolic switch in pancreatic cancer cells from oxidative phosphorylation to glycolysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2467.