Pancreatic cancer cells undergo extensive metabolic reprogramming to fulfil the demands of metabolic nutrients to fuel their rapid proliferation. This results in abnormal accumulation of various metabolites which causes both metabolic and nonmetabolic dysregulation and potential transformation to malignancy and therefore termed as “oncometabolites”. Hypoxia is a major hallmark of pancreatic tumors which associated with increase in self-renewal. The present study investigates the role of Hypoxia mediated altered oncometabolite in regulating self-renewal in pancreatic cancer. GC-mass spectrometric analysis of pancreatic cancer cells under hypoxia showed significant accumulation of 2-hydroxyglutarate (2-HG) both in cells and culture supernatant. Further analysis of hypoxic cells showed selective accumulation L- enantiomer form. Self-renewal requires critical balance between stemness and differentiation. Present study showed for the first time that L-2-HG regulates self-renewal by increasing expression of genes associated with stemness (Sox-2, CD133) and by decreasing expression of differentiation genes (PdX-1, HB9, NKX6.1). Further analysis showed that L-2-HG mediated epigenetic changes regulates these self-renewal gens in pancreatic cancer. Our results indicated that hypoxia mediated metabolic changes results in accumulation of L-2-HG which upregulate self-renewal by shifting critical balance of gene expression towards stemness in pancreatic cancer which contribute to chemoresistance and metastasis in Pancreatic cancer.

Citation Format: Vineet K. Gupta, Nikita Sharma, Kousik Kesh, Roey Hadad, Vikas Dudeja, Ashok Saluja, Sulagna Banerjee. Hypoxia promote self-renewal in pancreatic cancer by modulating L-2-Hydroxyglutarate level [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5284.