Non‐small cell lung cancer is characterized by dramatic changes in phospholipid profiles

Abstract

Non-small cell lung cancer (NSCLC) is the leading cause of cancer death globally. In order 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.

Myc Expression Drives Aberrant Lipid Metabolism in Lung Cancer

“…PIs are not considered to be rate-limiting for the formation of PIP n , and their roles in many cancers are yet to be defined. However, specific PIs have been proposed as biomarkers for prostate cancer (46), and have been shown to be elevated in human lung tumors (47). One possibility here is that PI may provide an alternative source of arachidonic acid, because the most abundant PI identified was arachidonatecontaining PI (38:4).…”

Application of proteomics in non-small-cell lung cancer

“…These lipid markers could indicate the presence and subtype of NSCLC, which present a potential for the development of diagnostic tools for NSCLC. [6] Using immunoprecipitation, matrix-assisted laser desorption/ ionization tandem time-of-flight MS and reverse-phase protein array analysis of lung cancer patients and healthy controls, calnexin has been identified as a new sero-diagnostic marker for early lung cancer. The calnexin expression levels were significantly higher in lung cancer patients and it was also detected in stage I disease.…”

Differential diagnosis of human lung tumors using surface desorption atmospheric pressure chemical ionization imaging mass spectrometry

“…[40][41][42][43][44] Lipid distributions in cancerous tissues have demonstrated to vary in composition from adjacent normal tissue. [40][41][42][43] Alterations in the phospholipids composition of tissues have been reported to a key signature for various certain cancer 45,46 and Alzheimer's diseases. 47 Determination of the spatial distribution of particular lipids in tissue sections has been demonstrated to be very important in tumor diagnosis and surgical resection.…”