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.