医学和肿瘤学中的主要问题是通过激活休眠癌细胞的癌症复发。与癌症休眠相关的代谢失调的系统量表检查为发现癌症精准医学的新分子靶标提供了希望。而且重要的是,用于预防癌症复发。在这项研究中,我们通过使用基于图形的方法将休眠癌细胞系和非休眠癌症对照的基于总mRNA测序的转录组数据映射到人类基因组规模的代谢网络上,和两种基于质量平衡的方法,一种基于反应活性/不活性,另一种基于通量变化。从基因表达综合(GSE83142和GSE114012)获得基因表达数据集。这项分析包括两种不同的癌症类型,液体和实体癌症,即,急性淋巴细胞白血病和结直肠癌。对于休眠的癌症状态,我们观察到三磷酸腺苷主要产生途径的变化,包括柠檬酸循环,氧化磷酸化,糖酵解/糖异生,表明休眠细胞的代谢重新编程,远离基于Warburg的能量代谢。所有三种计算方法都一致预测叶酸代谢,丙酮酸代谢,和谷氨酸代谢,以及缬氨酸/亮氨酸/异亮氨酸代谢在癌症休眠中可能失调。这些发现为癌症休眠提供了新的见解和分子途径靶标,全面分类休眠相关的代谢途径,并为未来的研究提供信息,特别是针对预防癌症复发的研究。
A major problem in medicine and oncology is cancer recurrence through the activation of dormant cancer cells. A system scale examination of metabolic dysregulations associated with the cancer dormancy offers promise for the discovery of novel molecular targets for cancer precision medicine, and importantly, for the prevention of cancer recurrence. In this study, we mapped the total mRNA sequencing-based transcriptomic data from dormant cancer cell lines and nondormant cancer controls onto a human genome-scale metabolic network by using a graph-based approach, and two mass balance-based approaches with one based on reaction activity/inactivity and the other one on flux changes. The gene expression datasets were accessed from Gene Expression Omnibus (GSE83142 and GSE114012). This analysis included two diverse cancer types, a liquid and a solid cancer, namely, acute lymphoblastic leukemia and colorectal cancer. For the dormant cancer state, we observed changes in major adenosine triphosphate-producing pathways, including the citric acid cycle, oxidative phosphorylation, and glycolysis/gluconeogenesis, indicating a reprogramming in the metabolism of dormant cells away from Warburg-based energy metabolism. All three computational approaches unanimously predicted that folate metabolism, pyruvate metabolism, and glutamate metabolism, as well as valine/leucine/isoleucine metabolism are likely dysregulated in cancer dormancy. These findings provide new insights and molecular pathway targets on cancer dormancy, comprehensively catalog dormancy-associated metabolic pathways, and inform future research aimed at prevention of cancer recurrence in particular.