脂质体
结直肠癌
鞘脂
脂类学
克拉斯
生物
癌症研究
CDKN2A
代谢组
医学
内科学
肿瘤科
癌症
生物信息学
代谢组学
遗传学
作者
Josef Ecker,Elisa Benedetti,Alida Kindt,Marcus Höring,Markus Perl,Andrea Christel Machmüller,Anna Sichler,Johannes Plagge,Yuting Wang,Sebastian Zeißig,Andrej Shevchenko,Ralph Burkhardt,Jan Krumsiek,Gerhard Liebisch,Klaus–Peter Janssen
标识
DOI:10.1053/j.gastro.2021.05.009
摘要
Lipidomic changes were causally linked to metabolic diseases, but the scenario for colorectal cancer (CRC) is less clear. We investigated the CRC lipidome for putative tumor-specific alterations through analysis of 3 independent retrospective patient cohorts from 2 clinical centers, to derive a clinically useful signature.Quantitative comprehensive lipidomic analysis was performed using direct infusion electrospray ionization coupled with tandem mass spectrometry (ESI-MS/MS) and high-resolution mass spectrometry (HR-MS) on matched nondiseased mucosa and tumor tissue in a discovery cohort (n = 106). Results were validated in 2 independent cohorts (n = 28, and n = 20), associated with genomic and clinical data, and lipidomic data from a genetic mouse tumor model (Apc1638N).Significant differences were found between tumor and normal tissue for glycero-, glycerophospho-, and sphingolipids in the discovery cohort. Comparison to the validation collectives unveiled that glycerophospholipids showed high interpatient variation and were strongly affected by preanalytical conditions, whereas glycero- and sphingolipids appeared more robust. Signatures of sphingomyelin and triacylglycerol (TG) species significantly differentiated cancerous from nondiseased tissue in both validation studies. Moreover, lipogenic enzymes were significantly up-regulated in CRC, and FASN gene expression was prognostically detrimental. The TG profile was significantly associated with postoperative disease-free survival and lymphovascular invasion, and was essentially conserved in murine digestive cancer, but not associated with microsatellite status, KRAS or BRAF mutations, or T-cell infiltration.Analysis of the CRC lipidome revealed a robust TG-species signature with prognostic potential. A better understanding of the cancer-associated glycerolipid and sphingolipid metabolism may lead to novel therapeutic strategies.
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