Abstract
BackgroundPancreatic 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.MethodsWe 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.ResultsWe 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.ConclusionsThe 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.
Highlights
Pancreatic cancer has a five-year survival rate of ~8%, with characteristic molecular heterogeneity and restricted treatment options
Targeting metabolism may be an effective therapeutic strategy for cancers that are driven by genetic alterations that are not tractable as direct drug targets [11, 19]
MtDNA sequencing in twelve Patient-derived cell line (PDCL) and matched normal DNA from each patient in the Australian Pancreatic Cancer Genome Initiative (APGI) cohort [31] identified 24 somatic mutations (Fig. 1b and Table 1)
Summary
Pancreatic cancer has a five-year survival rate of ~8%, with characteristic molecular heterogeneity and restricted treatment options. Along with established roles in driving cell proliferation and survival, KRAS and several other oncogenes (e.g., AKT) and tumour suppressors (e.g., TP53), have recently been shown to regulate metabolic pathways in pancreatic and other cancer cells [6,7,8] These metabolic changes include increased use of glutamine to support cell growth and proliferation, increased NADPH/NADP+ ratio to maintain cellular redox state [9] and rewiring anabolic glucose metabolism by inducing glucose uptake and enhancing glycolysis [10]. Glutamine can be used in place of glucose to fuel the TCA cycle, sparing glucose for glycolytic biosynthesis of cellular building blocks [18] The mechanisms underlying these metabolic shifts in different cancer types are not fully established, and are likely complex given the highly integrated nature of genes and signalling pathways regulating metabolism [17]. In the context of the very high penetrance of KRAS mutations in pancreatic cancers, targeting metabolic enzymes was effective in treating KRAS-mutant tumours in pre-clinical lung cancer models [12]
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