title: 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. 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.
authors.affiliation: Department of Oncology, Laboratory of Lipid Metabolism and Cancer, KU Leuven-University of Leuven, Leuven, Belgium.
authors.forename: Eyra
authors.initials: E
authors.lastname: Marien
authors.affiliation: Thoraxklinik at University Hospital Heidelberg, Translational Research Unit, Heidelberg, Germany.|TLRC-H - Translational Lung Research Center Heidelberg, Member of the German Center for Lung Research, Heidelberg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Meister
authors.affiliation: Thoraxklinik at University Hospital Heidelberg, Translational Research Unit, Heidelberg, Germany.|TLRC-H - Translational Lung Research Center Heidelberg, Member of the German Center for Lung Research, Heidelberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Muley
authors.affiliation: Department of Public Health and Primary Care, I-Biostat KU Leuven-University of Leuven and Universiteit Hasselt, Leuven, Belgium.
authors.forename: Steffen
authors.initials: S
authors.lastname: Fieuws
authors.affiliation: Department of Chemical and Biological Engineering, Systems Biology Group, Chalmers University of Technology, Gothenburg, Sweden.
authors.forename: Sergio
authors.initials: S
authors.lastname: Bordel
authors.affiliation: Department of Cellular and Molecular Medicine, Laboratory of Protein Phosphorylation and Proteomics, KU Leuven - University of Leuven, Leuven, Belgium.
authors.forename: Rita
authors.initials: R
authors.lastname: Derua
authors.affiliation: Department of Biochemistry and Mass Spectrometry Research Center, Vanderbilt University Medical Center, Nashville, TN.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Spraggins
authors.affiliation: Department of Biochemistry and Mass Spectrometry Research Center, Vanderbilt University Medical Center, Nashville, TN.|Delft University of Technology, Delft Center for Systems and Control, CD Delft, The Netherlands.
authors.forename: Raf
authors.initials: R
authors.lastname: Van de Plas
authors.affiliation: Department of Oncology, Laboratory of Lipid Metabolism and Cancer, KU Leuven-University of Leuven, Leuven, Belgium.
authors.forename: Jonas
authors.initials: J
authors.lastname: Dehairs
authors.affiliation: Department of Oncology, Laboratory of Lipid Metabolism and Cancer, KU Leuven-University of Leuven, Leuven, Belgium.
authors.forename: Jens
authors.initials: J
authors.lastname: Wouters
authors.affiliation: Department of Oncology, Laboratory of Lipid Metabolism and Cancer, KU Leuven-University of Leuven, Leuven, Belgium.
authors.forename: Muralidhararao
authors.initials: M
authors.lastname: Bagadi
authors.affiliation: TLRC-H - Translational Lung Research Center Heidelberg, Member of the German Center for Lung Research, Heidelberg, Germany.|Department of Surgery, Thoraxklinik at University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Dienemann
authors.affiliation: TLRC-H - Translational Lung Research Center Heidelberg, Member of the German Center for Lung Research, Heidelberg, Germany.|Department of Thoracic Oncology, Thoraxklinik at University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Thomas
authors.affiliation: TLRC-H - Translational Lung Research Center Heidelberg, Member of the German Center for Lung Research, Heidelberg, Germany.|University Hospital Heidelberg, Institute of Pathology, Heidelberg, Germany.
authors.forename: Philipp A
authors.initials: PA
authors.lastname: Schnabel
authors.affiliation: Department of Biochemistry and Mass Spectrometry Research Center, Vanderbilt University Medical Center, Nashville, TN.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Caprioli
authors.affiliation: Department of Cellular and Molecular Medicine, Laboratory of Protein Phosphorylation and Proteomics, KU Leuven - University of Leuven, Leuven, Belgium.
authors.forename: Etienne
authors.initials: E
authors.lastname: Waelkens
authors.affiliation: Department of Oncology, Laboratory of Lipid Metabolism and Cancer, KU Leuven-University of Leuven, Leuven, Belgium.
authors.forename: Johannes V
authors.initials: JV
authors.lastname: Swinnen
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000737:chemistry / Q000378:metabolism*; D010716:Phosphatidylinositols / Q000378:metabolism; D010743:Phospholipids / Q000737:chemistry / Q000378:metabolism*; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods; D013109:Sphingomyelins / Q000378:metabolism; D053719:Tandem Mass Spectrometry / Q000379:methods
chemical_list: D010716:Phosphatidylinositols; D010743:Phospholipids; D013109:Sphingomyelins
keywords: 2D-imaging MS; lipidomics; mass spectrometry; non-small cell lung cancer; phospholipids