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

Eyra Marien,Jonas Dehairs,Hendrik Dienemann,Michael Meister,Thomas Muley,Johannes V Swinnen,Jelle Machiels,Juan Carlos Lacal,Jeffrey M Spraggins,Richard M Caprioli,Rita Derua,Yinling Hu,Frank Vanderhoydonc,Raf Van De Plas,Philipp A Schnabel,Michael Thomas,Jami Willette-Brown,Etienne Waelkens,María Mercedes Binda ,Teresa Gómez Del Pulgar

doi:10.18632/oncotarget.7179

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-IkkαKA/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.

Highlights

Lung cancer is the deadliest type of cancer for both men and women [1]
To gain more insight into these changes and to identify specific pathways and enzymes driving these changes, we have further mined these data and have performed functional screenings by selective gene knockdown. These analyses reveal that acyl chain elongation is one of the most prominent pathways affected in lung squamous cell carcinoma (SCC) and pinpoint ELOVL6 as one of the main drivers of these changes and as potential target for antineoplastic intervention
Acyl chain elongation was found in 96.7% of SCCs, making it perhaps the most common cancer trait discovered so far

Summary

Introduction

Lung cancer is the deadliest type of cancer for both men and women [1]. Beyond the first line of therapy, few effective therapeutic options are available, for lung squamous cell carcinoma (SCC), which develops from the flat, surface-covering cells in the airways, and is one of the major lung cancer subtypes induced by smoking. Most efforts towards the identification of novel targets have focused on the molecular characterization of lung cancer at the level of the genome and transcriptome [2,3,4,5] Several of these studies have emphasized the heterogeneity of lung cancers characterized by scattered genetic traits and transcriptomic subtypes. To gain more insight into these changes and to identify specific pathways and enzymes driving these changes, we have further mined these data and have performed functional screenings by selective gene knockdown These analyses reveal that acyl chain elongation is one of the most prominent pathways affected in lung SCC and pinpoint ELOVL6 as one of the main drivers of these changes and as potential target for antineoplastic intervention

Methods

Results

Conclusion