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.

中文翻译：

---

胰腺癌的线粒体突变和代谢适应


背景胰腺癌的五年生存率约为 8%，具有特有的分子异质性和有限的治疗选择。靶向代谢已成为治疗胰腺癌等癌症的一种潜在有效的治疗策略，这些癌症是由基因改变驱动的，而基因改变不是可处理的药物靶标。尽管在各种肿瘤类型中都观察到了体细胞线粒体基因组 (mtDNA) 突变，但对代谢基因型-表型关系的了解仍然有限。方法我们对源自患者的胰腺癌细胞的独特队列采用了一种结合基因组学、代谢组学和表型分析的综合方法线（PDCL）。通过对线粒体基因组 (mtDNA) 以及编码线粒体成分和代谢基因的核基因进行靶向测序来进行基因组分析。 PDCL 的表型表征包括使用 Seahorse XF 细胞外通量分析仪测量细胞耗氧率 (OCR) 和细胞外酸化率 (ECAR)、靶向代谢组学和通路分析以及放射性标记的谷氨酰胺追踪。结果我们在 12 名患者的 mtDNA 中发现了 24 种体细胞突变。患者来源的胰腺癌细胞系（PDCL）。在一项针对约 1000 个对线粒体功能和代谢很重要的核基因的针对性研究中，又发现了 18 个突变。与参考数据集的比较表明，对具有预测功能效应的非同义突变体存在强烈的选择偏差。表型分析显示代谢变化与线粒体功能障碍一致，包括耗氧量减少和糖酵解增加。代谢组学和放射性标记底物示踪表明肿瘤中还原性谷氨酰胺代谢和脂质合成的启动。结论胰腺肿瘤的异质基因组景观可能会趋于共同的代谢表型，各个肿瘤通过不同的遗传机制适应增加的合成代谢需求。针对由此产生的代谢表型可能是一种有效的治疗策略。