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Targeting the mitochondrial pyruvate complex to alter metabolic programming in pancreatic ductal adenocarcinoma Ali, Hassan Asif


Pancreatic ductal adenocarcinoma (PDAC) can be stratified into distinct transcriptome based molecular subtypes, with the ‘basal-like’ (or ‘squamous’) subtype being associated with worse prognosis, compared to the ‘classical’ subtype. These subtypes are assigned based on Moffitt genes signature scores where scores above a threshold value are indictive of the basal-like subtype. Furthermore, PDAC tumours have unique metabolic transcriptomic profiles based on stratification of glycolytic and cholesterogenic genes which correlate with basal-like and classical gene expression patterns, respectively. The mitochondrial pyruvate complex (MPC) mediates the transport of pyruvate into the mitochondria. 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 tumours have lowest levels of MPC1 expression. Using PDAC tissue microarray data, our group found that reduced MPC1 protein expression correlates with reduced survival in patients. Therefore, we hypothesized that targeting MPC1 will alter metabolic reprogramming which may modulate tumour aggressiveness in tumour models. Genomically and clinically annotated patient-derived tumour organoids (PDOs) were generated from metastatic biopsies from patients enrolled in the PanGen study. Baseline metabolism and metabolic flux were measured using Seahorse XFe96 based glycolytic and mito stress tests, these testswere adapted for compatibility with PDOs. Baseline glycolysis and oxidative phosphorylation (OXPHOS) rates demonstrated high variability in glycolytic reserves highlighting the extent of metabolic reprogramming in PDOs. This variability in glycolytic reserve positively associated with Moffitt gene signature scores where PDOs with larger reserves tended to have higher Moffitt scores. To alter metabolic activity, eight PDOs were treated for 48 hours with UK-5099, a MPC1 inhibitor, or SRT-1720. SRT-1720 is an activator of sirtuin 1 (SIRT1) which deacetylates peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1𝛼), enhancing its activity. PGC1𝛼 has been shown to increase transcription of MPC1. Treatment with UK-5099 raised glycolysis and glycolytic capacity in four PDOs tested and reduced maximal respiration rates in seven PDOs. Treatment with SRT-1720 reduced glycolytic capacity in two PDOs but did not alter OXPHOS rates. Taken together, these results elicit the variability in metabolic dependency in PDOs to meet energy demands and the plasticity of metabolic reprogramming.

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