Marien Eyra, Meister Michael, Muley Thomas, Fieuws Steffen, Bordel Sergio, Derua Rita, Spraggins Jeffrey, Van de Plas Raf, Dehairs Jonas, Wouters Jens, Bagadi Muralidhararao, Dienemann Hendrik, Thomas Michael, Schnabel Philipp A, Caprioli Richard M, Waelkens Etienne, Swinnen Johannes V
Department of Oncology, Laboratory of Lipid Metabolism and Cancer, KU Leuven-University of Leuven, Leuven, Belgium.
Thoraxklinik at University Hospital Heidelberg, Translational Research Unit, Heidelberg, Germany.
Int J Cancer. 2015 Oct 1;137(7):1539-48. doi: 10.1002/ijc.29517. Epub 2015 Apr 7.
Non-small cell lung cancer (NSCLC) is the leading cause of cancer death globally. To develop better diagnostics and more effective treatments, research in the past decades has focused on identification of molecular changes in the genome, transcriptome, proteome, and more recently also the metabolome. Phospholipids, which nevertheless play a central role in cell functioning, remain poorly explored. Here, using a mass spectrometry (MS)-based phospholipidomics approach, we profiled 179 phospholipid species in malignant and matched non-malignant lung tissue of 162 NSCLC patients (73 in a discovery cohort and 89 in a validation cohort). We identified 91 phospholipid species that were differentially expressed in cancer versus non-malignant tissues. Most prominent changes included a decrease in sphingomyelins (SMs) and an increase in specific phosphatidylinositols (PIs). Also a decrease in multiple phosphatidylserines (PSs) was observed, along with an increase in several phosphatidylethanolamine (PE) and phosphatidylcholine (PC) species, particularly those with 40 or 42 carbon atoms in both fatty acyl chains together. 2D-imaging MS of the most differentially expressed phospholipids confirmed their differential abundance in cancer cells. We identified lipid markers that can discriminate tumor versus normal tissue and different NSCLC subtypes with an AUC (area under the ROC curve) of 0.999 and 0.885, respectively. In conclusion, using both shotgun and 2D-imaging lipidomics analysis, we uncovered a hitherto unrecognized alteration in phospholipid profiles in NSCLC. These changes may have important biological implications and may have significant potential for biomarker development.
非小细胞肺癌（NSCLC）是全球癌症死亡的主要原因。为了开发更好的诊断方法和更有效的治疗方法，过去几十年的研究集中在识别基因组、转录组、蛋白质组以及最近的代谢组中的分子变化。然而，在细胞功能中起核心作用的磷脂，其研究仍很不足。在这里，我们使用基于质谱（MS）的磷脂组学方法，对162例NSCLC患者（发现队列73例，验证队列89例）的恶性和配对的非恶性肺组织中的179种磷脂种类进行了分析。我们鉴定出91种在癌组织与非恶性组织中差异表达的磷脂种类。最显著的变化包括鞘磷脂（SMs）减少，特定磷脂酰肌醇（PIs）增加。还观察到多种磷脂酰丝氨酸（PSs）减少，同时几种磷脂酰乙醇胺（PE）和磷脂酰胆碱（PC）种类增加，特别是那些两条脂肪酰链中都含有40或42个碳原子的种类。对差异表达最明显的磷脂进行二维成像质谱分析，证实了它们在癌细胞中的丰度差异。我们鉴定出能够区分肿瘤组织与正常组织以及不同NSCLC亚型的脂质标志物，其ROC曲线下面积（AUC）分别为0.999和0.885。总之，通过鸟枪法和二维成像脂质组学分析，我们发现了NSCLC中磷脂谱迄今未被认识的改变。这些变化可能具有重要的生物学意义，并且在生物标志物开发方面可能具有巨大潜力。
