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 

机构地区：[1]Key Laboratory of Breast Cancer in Shanghai,Department of Breast Surgery,Fudan University Shanghai Cancer Center,Department of Oncology,Shanghai Medical College,Fudan University,Shanghai,China. [2]Human Phenome Institute,Fudan University,Shanghai,China. [3]Department of Pathology,University of Texas Southwestern Medical Center,Dallas,TX,USA. [4]Predictive Oncology team,Centre de Recherche en Cancérologie de Marseille(CRCM),INSERM UMR1068,CNRS UMR725,Aix-Marseille Université,Institut PaoliCalmettes,Marseille,France. [5]Department of Industrial Systems Engineering and Management,National University of Singapore,Singapore,Singapore

出　　处：《Cell Research》2022年第5期477-490,共14页细胞研究（英文版）

基　　金：the National Key R&D Project of China(2020YFA0112304),the National Natural Science Foundation of China(81922048,82002792,82002802,82072922 and 91959207);the Program of Shanghai Academic/Technology Research Leader(20XD1421100);the Shanghai Key Laboratory of Breast Cancer(12DZ2260100);the Clinical Research Plan of SHDC(SHDC2020CR4002,SHDC2020CR5005);Shanghai Sailing Program(20YF1408600 and 20YF1408700)。

摘　　要：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-glutamate is a crucial tumor-promoting metabolite and potential therapeutic target for high-risk BLIS tumors.Together,our study reveals the clinical significance of TNBC metabolomics,which can not only optimize the transcriptomic subtyping system,but also suggest novel therapeutic targets.This metabolomic dataset can serve as a useful public resource to promote precision treatment of TNBC.

关 键 词：BREAST LINKING TOGETHER 

分 类 号：R73[医药卫生—肿瘤]