Creatine riboside is a cancer cell-derived metabolite associated with arginine auxotrophy.
Creatine riboside is a cancer cell-derived metabolite associated with arginine auxotrophy.
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DOI：
10.1172/jci157410
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发表时间：
2022-07-15
影响因子：
15.9
通讯作者：
Harris, Curtis C.
中科院分区：
文献类型：
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作者：
Parker, Amelia L.;Toulabi, Leila;Oike, Takahiro;Kanke, Yasuyuki;Patel, Daxeshkumar;Tada, Takeshi;Taylor, Sheryse;Beck, Jessica A.;Bowman, Elise;Reyzer, Michelle L.;Butcher, Donna;Kuhn, Skyler;Pauly, Gary T.;Krausz, Kristopher W.;Gonzalez, Frank J.;Hussain, S. Perwez;Ambs, Stefan;Ryan, Brid M.;Wang, Xin Wei;Harris, Curtis C.
癌细胞的代谢依赖性有很大的潜力被利用来改善癌症的诊断和治疗。肌酸核糖体（CR）被认为是一种与肺癌和肝癌的风险和预后相关的尿液代谢物。然而，癌症患者中高CR水平的来源及其对这些侵袭性癌症治疗的影响尚不清楚。通过整合肺癌和肝癌的多组学数据，我们发现CR是癌细胞衍生的代谢物。人类肿瘤的全球代谢组学和基因表达分析以及匹配的液体活检，以及功能研究显示，线粒体尿素循环失调和核苷酸失衡与高CR水平和预后不良的指标相关。这种代谢表型与免疫浸润减少有关，并支持癌细胞快速增殖，从而驱动侵袭性肿瘤生长。CRhi癌细胞对精氨酸缺乏营养，揭示了一种可能用于治疗的代谢脆弱性。这凸显了CR的潜力，它不仅可以作为一种预后不良的生物标志物，还可以作为一种伴生生物标志物，为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。
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.