Mitochondrial mutations and metabolic adaptation in pancreatic cancer.

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dc.creatorHardie, Rae-Anne
dc.creatorvan Dam, Ellen
dc.creatorCowley, Mark
dc.creatorHan, Ting-Li
dc.creatorBalaban, Seher
dc.creatorPajic, Marina
dc.creatorPinese, Mark
dc.creatorIconomou, Mary
dc.creatorShearer, Robert F
dc.creatorMcKenna, Jessie
dc.creatorMiller, David
dc.creatorWaddell, Nicola
dc.creatorPearson, John V
dc.creatorGrimmond, Sean M
dc.creatorAustralian Pancreatic Cancer Genome Initiative
dc.creatorSazanov, Leonid
dc.creatorBiankin, Andrew V
dc.creatorVillas-Boas, Silas
dc.creatorHoy, Andrew J
dc.creatorTurner, Nigel
dc.creatorSaunders, Darren N
dc.date2017-01-31T07:03:25Z
dc.date2017-01-31T07:03:25Z
dc.date2017
dc.date2017-01-31T07:03:24Z
dc.date.accessioned2026-08-03T02:32:21Z
dc.descriptionBACKGROUND: Pancreatic cancer has a five-year survival rate of ~8%, with characteristic molecular heterogeneity and restricted treatment options. Targeting metabolism has emerged as a potentially effective therapeutic strategy for cancers such as pancreatic cancer, which are driven by genetic alterations that are not tractable drug targets. Although somatic mitochondrial genome (mtDNA) mutations have been observed in various tumors types, understanding of metabolic genotype-phenotype relationships is limited. METHODS: We deployed an integrated approach combining genomics, metabolomics, and phenotypic analysis on a unique cohort of patient-derived pancreatic cancer cell lines (PDCLs). Genome analysis was performed via targeted sequencing of the mitochondrial genome (mtDNA) and nuclear genes encoding mitochondrial components and metabolic genes. Phenotypic characterization of PDCLs included measurement of cellular oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) using a Seahorse XF extracellular flux analyser, targeted metabolomics and pathway profiling, and radiolabelled glutamine tracing. RESULTS: We identified 24 somatic mutations in the mtDNA of 12 patient-derived pancreatic cancer cell lines (PDCLs). A further 18 mutations were identified in a targeted study of ~1000 nuclear genes important for mitochondrial function and metabolism. Comparison with reference datasets indicated a strong selection bias for non-synonymous mutants with predicted functional effects. Phenotypic analysis showed metabolic changes consistent with mitochondrial dysfunction, including reduced oxygen consumption and increased glycolysis. Metabolomics and radiolabeled substrate tracing indicated the initiation of reductive glutamine metabolism and lipid synthesis in tumours. CONCLUSIONS: The heterogeneous genomic landscape of pancreatic tumours may converge on a common metabolic phenotype, with individual tumours adapting to increased anabolic demands via different genetic mechanisms. Targeting resulting metabolic phenotypes may be a productive therapeutic strategy.
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dc.identifierCancer & Metabolism. 2017 Jan 30;5(1):2
dc.identifier2049-3002
dc.identifierhttps://www.repository.cam.ac.uk/handle/1810/262183
dc.identifier10.17863/CAM.7440
dc.identifier2049-3002
dc.identifier.urihttps://repo.dare.co.zw/handle/123456789/167352
dc.languageeng
dc.languageen
dc.publisherSpringer Nature
dc.publisherhttps://doi.org/10.1186/s40170-017-0164-1
dc.rightsAll Rights Reserved
dc.rightshttps://www.rioxx.net/licenses/all-rights-reserved/
dc.rightsThe Author(s).
dc.subjectGenome
dc.subjectGlutamine
dc.subjectLipid
dc.subjectMetabolomics
dc.subjectMitochondria
dc.subjectPancreas
dc.titleMitochondrial mutations and metabolic adaptation in pancreatic cancer.
dc.typeArticle

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