Phospholipid profiling identifies acyl chain elongation as a ubiquitous trait and potential target for the treatment of lung squamous cell carcinoma
Eyra Marien (Katholieke Universiteit Leuven)
Michael Meister (Heidelberg University Hospital)
Thomas Muley (Heidelberg University Hospital)
Teresa Gomez del Pulgar (Division of Translational Oncology)
Rita Derua (Katholieke Universiteit Leuven)
Jeffrey M. Spraggins (Mass Spectrometry Research Center)
Raf Van De Plas (TU Delft - Team Raf Van de Plas, VanderBilt University)
Frank Vanderhoydonc (Katholieke Universiteit Leuven)
Jelle Machiels (Katholieke Universiteit Leuven)
Maria Mercedes Binda (Katholieke Universiteit Leuven)
Jonas Dehairs (Katholieke Universiteit Leuven)
Jami Willette-Brown (National Cancer Institute)
Yinling Hu (National Cancer Institute)
Hendrik Dienemann (Member of the German Center for Lung Research, Heidelberg University Hospital)
Michael Thomas (Member of the German Center for Lung Research, Heidelberg University Hospital)
Philipp A. Schnabe (Member of the German Center for Lung Research, Saarland University)
Richard M. Caprioli (Mass Spectrometry Research Center)
Juan Carlos Lacal (Division of Translational Oncology)
Etienne Waelkens (Katholieke Universiteit Leuven)
Johannes V. Swinnen (Katholieke Universiteit Leuven)
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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-IkkaKA/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.