代谢组学
胰腺癌
奥沙利铂
抗药性
吉西他滨
医学
药品
表型
转录组
内科学
多西紫杉醇
肿瘤科
癌症研究
药理学
生物信息学
生物
癌症
结直肠癌
基因
基因表达
微生物学
生物化学
作者
Abdessamad El Kaoutari,Nicolás A. Fraunhoffer,Owen Hoare,Carlos Teyssedou,Philippe Soubeyran,Odile Gayet,Julie Roques,Gwen Lomberk,Raúl Urrutia,Nelson Dusetti,Juan Iovanna
出处
期刊:EBioMedicine
[Elsevier]
日期:2021-04-01
卷期号:66: 103332-103332
被引量:24
标识
DOI:10.1016/j.ebiom.2021.103332
摘要
BackgroundAlthough significant advances have been made recently to characterize the biology of pancreatic ductal adenocarcinoma (PDAC), more efforts are needed to improve our understanding and to face challenges related to the aggressiveness, high mortality rate and chemoresistance of this disease.MethodsIn this study, we perform the metabolomics profiling of 77 PDAC patient-derived tumor xenografts (PDTX) to investigate the relationship of metabolic profiles with overall survival (OS) in PDAC patients, tumor phenotypes and resistance to five anticancer drugs (gemcitabine, oxaliplatin, docetaxel, SN-38 and 5-Fluorouracil).FindingsWe identified a metabolic signature that was able to predict the clinical outcome of PDAC patients (p < 0.001, HR=2.68 [95% CI: 1.5–4.9]). The correlation analysis showed that this metabolomic signature was significantly correlated with the PDAC molecular gradient (PAMG) (R = 0.44 and p < 0.001) indicating significant association to the transcriptomic phenotypes of tumors. Resistance score established, based on growth rate inhibition metrics using 35 PDTX-derived primary cells, allowed to identify several metabolites related to drug resistance which was globally accompanied by accumulation of several diacy-phospholipids and decrease in lysophospholipids. Interestingly, targeting glycerophospholipid synthesis improved sensitivity to the three tested cytotoxic drugs indicating that interfering with metabolism could be a promising therapeutic strategy to overcome the challenging resistance of PDAC.InterpretationIn conclusion, this study shows that the metabolomic profile of pancreatic PDTX models is strongly associated to clinical outcome, transcriptomic phenotypes and drug resistance. We also showed that targeting the lipidomic profile could be used in combinatory therapies against chemoresistance in PDAC.
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