Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute (NCI), NIH, Bethesda, Maryland, USA.
National Research Resource for Imaging Mass Spectrometry, Vanderbilt University, Nashville, Tennessee, USA.
J Clin Invest. 2022 Jul 15;132(14). doi: 10.1172/JCI157410.
The metabolic dependencies of cancer cells have substantial potential to be exploited to improve the diagnosis and treatment of cancer. Creatine riboside (CR) is identified as a urinary metabolite associated with risk and prognosis in lung and liver cancer. However, the source of high CR levels in patients with cancer as well as their implications for the treatment of these aggressive cancers remain unclear. By integrating multiomics data on lung and liver cancer, we have shown that CR is a cancer cell-derived metabolite. Global metabolomics and gene expression analysis of human tumors and matched liquid biopsies, together with functional studies, revealed that dysregulation of the mitochondrial urea cycle and a nucleotide imbalance were associated with high CR levels and indicators of a poor prognosis. This metabolic phenotype was associated with reduced immune infiltration and supported rapid cancer cell proliferation that drove aggressive tumor growth. CRhi cancer cells were auxotrophic for arginine, revealing a metabolic vulnerability that may be exploited therapeutically. This highlights the potential of CR not only as a poor-prognosis biomarker but also as a companion biomarker to inform the administration of arginine-targeted therapies in precision medicine strategies to improve survival for patients with cancer.
癌细胞的代谢依赖性具有很大的潜力，可以被利用来改善癌症的诊断和治疗。肌酸核苷 (CR) 被鉴定为与肺癌和肝癌的风险和预后相关的尿代谢物。然而，癌症患者中高 CR 水平的来源以及它们对这些侵袭性癌症治疗的影响仍不清楚。通过整合肺癌和肝癌的多组学数据，我们已经表明 CR 是一种癌细胞衍生的代谢物。对人类肿瘤和匹配的液体活检进行的全局代谢组学和基因表达分析，以及功能研究，揭示了线粒体尿素循环和核苷酸失衡的失调与高 CR 水平和预后不良的指标有关。这种代谢表型与免疫浸润减少有关，并支持快速的癌细胞增殖，从而推动侵袭性肿瘤生长。CRhi 癌细胞对精氨酸具有营养依赖性，这揭示了一种代谢脆弱性，可能具有治疗潜力。这突出了 CR 的潜力，不仅可以作为预后不良的生物标志物，还可以作为伴随的生物标志物，为精准医学策略中精氨酸靶向治疗的管理提供信息，以提高癌症患者的生存率。
