Comprehensive metabolomics expands precision medicine for triple-negative breast cancer

作者：Yi Xiao, Ding Ma, Yun‐Song Yang, Fan Yang, Jia-Han Ding, Yue Gong, Lin Jiang, Li‐Ping Ge, Song‐Yang Wu, Qiang Yu, Qing Zhang, François Bertucci, Qiuzhuang Sun, Xin Hu, Da‐Qiang Li, Zhi‐Ming Shao, Yi‐Zhou Jiang · 发表于：Cell Research · 年份：2022 · DOI：10.1038/s41422-022-00614-0 · 被引用次数：332 · 研究领域：Immune cells in cancer、Cancer, Hypoxia, and Metabolism、Sphingolipid Metabolism and Signaling

Metabolic reprogramming is a hallmark of cancer. However, systematic characterizations of metabolites in triple-negative breast cancer (TNBC) are still lacking. Our study profiled the polar metabolome and lipidome in 330 TNBC samples and 149 paired normal breast tissues to construct a large metabolomic atlas of TNBC. Combining with previously established transcriptomic and genomic data of the same cohort, we conducted a comprehensive analysis linking TNBC metabolome to genomics. Our study classified TNBCs into three distinct metabolomic subgroups: C1, characterized by the enrichment of ceramides and fatty acids; C2, featured with the upregulation of metabolites related to oxidation reaction and glycosyl transfer; and C3, having the lowest level of metabolic dysregulation. Based on this newly developed metabolomic dataset, we refined previous TNBC transcriptomic subtypes and identified some crucial subtype-specific metabolites as potential therapeutic targets. The transcriptomic luminal androgen receptor (LAR) subtype overlapped with metabolomic C1 subtype. Experiments on patient-derived organoid and xenograft models indicate that targeting sphingosine-1-phosphate (S1P), an intermediate of the ceramide pathway, is a promising therapy for LAR tumors. Moreover, the transcriptomic basal-like immune-suppressed (BLIS) subtype contained two prognostic metabolomic subgroups (C2 and C3), which could be distinguished through machine-learning methods. We show that N-acetyl-aspartyl-glut...