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Project

Lipid profiling of cancer tissue: possibilities for cancer subtyming and applications for diagnosis and therapy.

Lung cancer is the deadliest of all cancers in the world. Particularly non-small cell lung cancer (NSCLC) is very prevalent and accounts for 80% of all lung cancer cases. One of the key problems in the management of NSCLC is the high failure rate of existing treatments, urging the need for new molecular biomarkers and novel therapeutic targets. So far, most efforts towards this molecular characterization have been carried out at the level of the genome, transcriptome, proteome, and lately also the metabolome. The lipidome and particularly the phospholipidome remain, however, largely unexplored. Nevertheless, phospholipids, as being the most important components of cellular membranes, play a central role in cell biology. Moreover, the phospholipidome is located at the far end of the gene regulatory cascade and for that reason integrates information at several levels, including genetics and gene expression. In addition, development and progression of cancer, and lung cancer, is frequently associated with alterations in lipid metabolism in tumor cells. Therefore, we explored in this thesis to what extent the development of lung cancer is accompanied by changes in phospholipid profiles and tried to get more insight in the nature and the consequences of these changes. We investigated their potential as biomarkers or targets for a more efficient treatment of lung cancer in the future.

In the first part of this doctoral project, we have used an in-house developed shotgun electrospray ionization tandem mass spectrometry (ESI-MS/MS) approach to study alterations in phospholipid profiles in lung cancer. 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 an increase in specific phosphatidylinositols (PIs) as well as long phosphatidylethanolamines (PEs) and phosphatidylcholines (PCs) (≥40 carbons in the two acyl chains together) in tumor tissue, along with a general decrease in all sphingomyelins (SMs) and in multiple phosphatidylserine (PS) species. 2D-imaging MS of the most differentially expressed phospholipids confirmed their differential abundance in cancer cells. Moreover, 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. These data demonstrate that lung cancer tissue has a dramatically different phospholipid composition compared to normal tissue. These findings are very important for the further exploration of altered lipid metabolism in lung cancer, and may hold significant potential for the development of biomarkers.

In the second part of this doctoral project, we focused on one specific aspect of the data we obtained in our initial lipidomics analysis, i.e. the increase in phospholipid species with long fatty acyl chains that was observed in NSCLC tissue compared to matched normal tissue. We found that the large majority (96.7%) of human squamous cell carcinomas (SCCs) and to a lesser extent (82.9%) adenocarcinomas (ADs) contain phospholipids with longer acyl chains compared to matched normal tissues. Also here, we performed 2D-imaging MS to confirm that tumor tissue and particularly tumor cells have longer phospholipids than the non-malignant counterparts. This trait was also found in a knock-in mouse model of lung SCC. We identified ELOVL6 (elongation of very long fatty acids 6) as the main elongation enzyme responsible for acyl chain elongation in cancer cells. Inhibition of ELOVL6 markedly reduced colony formation in soft agar and attenuated tumor growth in a syngeneic mouse model in vivo. These findings reveal acyl chain elongation as one of the most common traits of lung cancer discovered so far and identify ELOVL6 as a novel potential target for cancer intervention.

Taken together, the findings in this thesis provide significant novel insights into the field of lipid biology and lung cancer and may provide the basis for the development of novel diagnostic cancer markers and for novel more common therapeutic approaches targeting lipid metabolism in lung cancer in the future.

Date:1 Oct 2010 →  23 Sep 2015
Keywords:Phospholipidome, Cancer, Membrane
Disciplines:Systems biology, Medical biochemistry and metabolism, Biochemistry and metabolism, Morphological sciences, Oncology
Project type:PhD project