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.

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;Francois Bertucci;Qiuzhuang Sun;Xin Hu;Da-Qiang Li;Zhi-Ming Shao;Yi-Zhou Jiang

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;Human Phenome Institute,Fudan University,Shanghai,China;Department of Pathology,University of Texas Southwestern Medical Center,Dallas,TX,USA;Predictive Oncology team,Centre de Recherche en Cancérologie de Marseille(CRCM),INSERM UMR1068,CNRS UMR725,Aix-Marseille Université,Institut Paoli-Calmettes,Marseille,France;Department of Industrial Systems Engineering and Management,National University of Singapore,Singapore,Singapore

细胞研究（英文版）

[1]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;Francois Bertucci;Qiuzhuang Sun;Xin Hu;Da-Qiang Li;Zhi-Ming Shao;Yi-Zhou Jiang-.Comprehensive metabolomics expands precision medicine for triple-negative breast cancer)[J].细胞研究（英文版）,2022(05):477-490

TNBCs,ceramides,BLIS,aspartyl

Comprehensive,metabolomics,expands,precision,medicine,triple,negative,breast,cancer,Metabolic,reprogramming,hallmark,However,systematic,characterizations,metabolites,are,still,lacking,Our,study,profiled,polar,metabolome,lipidome,samples,paired,normal,tissues,construct,large,atlas,Combining,previously,established,transcriptomic,same,cohort,conducted,comprehensive,analysis,linking,genomics,classified,into,three,distinct,subgroups,C1,characterized,by,enrichment,fatty,acids,C2,featured,upregulation,related,oxidation,reaction,glycosyl,transfer,C3,having,lowest,level,metabolic,dysregulation,Based,this,newly,developed,dataset,refined,subtypes,identified,some,crucial,specific,potential,therapeutic,targets,luminal,androgen,receptor,LAR,overlapped,Experiments,patient,derived,organoid,xenograft,models,indicate,that,targeting,sphingosine,phosphate,S1P,intermediate,pathway,promising,therapy,tumors,Moreover,basal,like,immune,suppressed,contained,two,prognostic,which,could,be,distinguished,through,machine,learning,methods,We,show,acetyl,glutamate,promoting,high,risk,Together,reveals,clinical,significance,not,only,optimize,subtyping,but,also,suggest,novel,This,serve,useful,public,resource,promote,treatment

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