Phospholipid profiling identifies acyl chain elongation as a ubiquitous trait and potential target for the treatment of lung squamous cell carcinoma

// Eyra Marien 1 , Michael Meister 2,3 , Thomas Muley 2,3 , Teresa Gomez del Pulgar 4 , Rita Derua 5 , Jeffrey M. Spraggins 6 , Raf Van de Plas 6,7 , Frank Vanderhoydonc 1 , Jelle Machiels 1 , Maria Mercedes Binda 8 , Jonas Dehairs 1 , Jami Willette-Brown 9 , Yinling Hu 9 , Hendrik Dienemann 3,10 , Michael Thomas 3,11 , Philipp A. Schnabel 3,12 , Richard M. Caprioli 6 , Juan Carlos Lacal 4 , Etienne Waelkens 5 and Johannes V. Swinnen 1 1 KU Leuven – University of Leuven, LKI - Leuven Cancer Institute, Department of Oncology, Laboratory of Lipid Metabolism and Cancer, Leuven, Belgium 2 Thoraxklinik at University Hospital Heidelberg, Translational Research Unit, Heidelberg, Germany 3 TLRC-H – Translational Lung Research Center Heidelberg, Member of The German Center for Lung Research, Heidelberg, Germany 4 Fundacion Jimenez Diaz, Division of Translational Oncology, Madrid, Spain 5 KU Leuven – University of Leuven, Department of Cellular and Molecular Medicine, Laboratory of Protein Phosphorylation and Proteomics, Leuven, Belgium 6 Vanderbilt University Medical Center, Department of Biochemistry and Mass Spectrometry Research Center, Nashville, TN, USA 7 Delft University of Technology, Delft Center for Systems and Control, Delft, The Netherlands 8 KU Leuven – University of Leuven, LKI - Leuven Cancer Institute, Department of Oncology, Abdominal Surgical Oncology, Leuven, Belgium 9 National Cancer Institute, Centre for Cancer Research, Cancer and Inflammation Program, Frederick, MD, USA 10 Thoraxklinik at University Hospital Heidelberg, Department of Surgery, Heidelberg, Germany 11 Thoraxklinik at University Hospital Heidelberg, Department of Thoracic Oncology, Heidelberg, Germany 12 University of The Saarland, Institut fur Allgemeine und Spezielle Pathologie, Homburg/Saar, Germany Correspondence to: Johannes V. Swinnen, email: // Keywords : lipidomics, phospholipids, cancer, ELOVL, lung SCC Received : December 17, 2015 Accepted : January 04, 2016 Published : February 03, 2016 Abstract Lung cancer is the leading cause of cancer death. Beyond first line treatment, few therapeutic options are available, particularly for squamous cell carcinoma (SCC). Here, we have explored the phospholipidomes of 30 human SCCs and found that they almost invariably (in 96.7% of cases) contain phospholipids with longer acyl chains compared to matched normal tissues. This trait was confirmed using in situ 2D-imaging MS on tissue sections and by phospholipidomics of tumor and normal lung tissue of the L-Ikkα KA/KA mouse model of lung SCC. In both human and mouse, the increase in acyl chain length in cancer tissue was accompanied by significant changes in the expression of acyl chain elongases (ELOVLs). Functional screening of differentially expressed ELOVLs by selective gene knockdown in SCC cell lines followed by phospholipidomics revealed ELOVL6 as the main elongation enzyme responsible for acyl chain elongation in cancer cells. Interestingly, inhibition of ELOVL6 drastically reduced colony formation of multiple SCC cell lines in vitro and significantly attenuated their growth as xenografts in vivo in mouse models. These findings identify acyl chain elongation as one of the most common traits of lung SCC discovered so far and pinpoint ELOVL6 as a novel potential target for cancer intervention.