Poster Presentation 25th Lorne Cancer Conference 2013

Mitochondrial Mutations and Metabolic Profiling of Pancreatic Cancer (#198)

Rae-Anne Hardie 1 , Mary Iconomou 1 , Robert Shearer 1 , Marina Pajic 1 , Andrew V Biankin 1 , Sean M Grimmond 2 , Mark Cowley 1 , Warren Kaplan 3 , Vanessa M Hayes 4 , Nigel Turner 5 , Darren N Saunders 1
  1. Cancer, Kinghorn Cancer Centre and Garvan Institute, Darlinghurst, Australia
  2. The University of Queensland, Institute for Molecular Bioscience, Brisbane, Australia
  3. Garvan Institute, Darlinghurst, NSW, Australia
  4. Genomic Medicine, J. Craig Venter Institute, La Jolla, USA
  5. Diabetes and Obesity, Garvan Institute, Darlinghurst, Australia

Pancreatic cancer has a devastating prognosis, with five-year survival only 5%. Exacerbating factors include the heterogeneity between individual cancers, lack of early screening, and scarcity of appropriate treatment. The role of metabolic reprogramming, where biosynthesis and maintenance of redox capacity is favoured over energy production, has attracted renewed interest in understanding tumourigenesis, and as a potential therapeutic target. Further, many tumours exhibit accumulation of mitochondrial mutations, but little work has been done linking these observations to phenotypic changes through functional studies. Using a unique panel of patient-derived pancreatic cancer cell lines, we identified numerous somatic mutations in the mitochondrial genome. Most were non-synonymous and located in coding regions for electron transport chain (ETC) subunits or in important control regions. Interestingly, analysis of 1400 nuclear genes encoding mitochondrial proteins revealed only one mutation in the same tumour panel. Interestingly, we observed differences in expression of mitochondrial electron transport chain subunits, and ETC complex assembly as measured by Blue Native PAGE. Oxygen consumption, Seahorse and metabolomics showed significant variation in metabolic phenotype between normal pancreatic and tumour cells. We are now exploring metabolic flux and control in these tumours. Using this systematic approach to define the role of metabolic reprogramming in pancreatic cancer, and the relative contribution of mitochondrial somatic mutations to these phenotypes we aim to identify common pathways that may be targeted therapeutically.