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

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.

Hyper-Elongation in Colorectal Cancer Tissue – Cerotic Acid is a Potential Novel Serum Metabolic Marker of Colorectal Malignancies

“…Enhanced elongation of FAs has been already documented in other malignancies. Recently, Marien et al [12] revealed overexpression of ELOVL6 in SCC, and demonstrated that inhibition of this enzyme decreased proliferation rate of SCC cell lines in vitro and their growth in an in vivo mouse model. These results suggest that ELOVL6 may play a critical role in the development and metabolism of cancer cells.…”

“…The underlying mechanism of FA hyper-elongation in CRC specimens is still to be understood. According to Marien et al [12], VLCFAs may play an important role in maintaining the structure and thickness of plasma membranes, and contribute considerably to the topology and/or activity of the membrane proteins.…”

“…ELOVL6 is the main enzyme of elongase family, playing an established role in energy metabolism and development of insulin sensitivity [11]. Recently, Marien et al [12] demonstrated that an increase in acyl chain length in lung cancer tissue of human and mouse is associated with significantly elevated expression of acyl chain elongases, especially ELOVL6. Inhibition of ELOVL6 was shown to significantly reduce the proliferation of squamous cell carcinoma (SCC) cell lines in vitro and to attenuate their growth as a xenograft in an in vivo mouse model [12].…”

“…Recently, Marien et al [12] demonstrated that an increase in acyl chain length in lung cancer tissue of human and mouse is associated with significantly elevated expression of acyl chain elongases, especially ELOVL6. Inhibition of ELOVL6 was shown to significantly reduce the proliferation of squamous cell carcinoma (SCC) cell lines in vitro and to attenuate their growth as a xenograft in an in vivo mouse model [12]. However, to the best of our knowledge, none of the previous studies analyzed FA elongation in CRC tissue.…”

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.…”