Abstract PO-021: Targeting the mitochondrial pyruvate complex to alter metabolic programming in pancreatic cancer

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDAC) can be stratified into distinct transcriptome subtypes, with the ‘basal-like’ or ‘squamous’ subtype being associated with worse prognosis, compared to the ‘classical’ subtype. Our group recently demonstrated that PDAC tumors have unique metabolic transcriptome profiles, and that genes involved in glycolysis and cholesterol synthesis pathways are positively correlated with basal-like and classical gene expression patterns, respectively. The mitochondrial pyruvate complex (MPC) mediates the transport of pyruvate into the mitochondria which attenuates the effect of glycolysis on tumor progression. The mitochondrial pyruvate carrier 1 (MPC1) gene, which encodes one of two subunits of MPC, is deleted in over 60% of metastatic PDAC and PDAC glycolytic tumors have lowest levels of MPC1 expression. Using PDAC tissue microarrays, we also found that reduced MPC1 protein expression correlates with reduced survival in patients. We hypothesized that targeting MPC1 will alter metabolic reprogramming and may modulate tumor aggressiveness and therapeutic vulnerability in PDAC tumor cells. Genomically and clinically annotated patient-derived tumor organoids (PDOs) were generated from metastatic biopsies from patients enrolled in the PanGen study (NCT02869802). PDOs from both basal and classical tumors were used in the study. In order to investigate glycolysis in PDOs, we adapted the Seahorse Glycolytic Stress Test. Glycolysis, glycolytic capacity and reserve were analyzed in PDOs under basal and treated conditions. To alter MPC1 activity, PDOs were treated for 48 hours with 5uM of UK-5099, an MPC1 inhibitor, or 2.5-5uM SRT1720. SRT1720 is an activator of sirtuin 1 (SIRT1) and the transcriptional coactivator peroxisome proliferator-activated receptor γ coactivator-1α (PGC1-α), which regulates the expression of MPC1. An unpaired t-test with an alpha of 0.05 was used for all statistical analysis. Glycolysis analysis revealed distinct glycolytic profiles in PDOs with differences in glycolytic capacity and reserves trending with different tumor subtypes. Treatment with UK-5099 resulted in an increase in both glycolytic rate and reserve in PDOs from basal and classical tumors. Treatment with SRT1720 resulted in significantly reduced glycolytic rate and capacity. These data suggest that PDAC PDOs exhibit distinct metabolic profiles and that targeting MPC1 can modulate glycolysis in PDOs. Our ongoing efforts aim to further characterize the subtype-specific effect of MPC1 modulators on glycolysis and chemotherapy response in PDAC PDOs. Citation Format: Hassan A. Ali, Andrew Metcalfe, James T. Topham, Cassia S. Warren, Joanna M. Karasinska, David F. Schaeffer, Daniel J. Renouf. Targeting the mitochondrial pyruvate complex to alter metabolic programming in pancreatic cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-021.