The colorectal cancer lipidome - identification of a robust tumor-specific lipid species signature.

ABSTRACT Objective Lipidomic changes were causally linked to metabolic diseases, but the scenario for colorectal cancer (CRC) is less clear. We investigated the CRC lipidome for putative tumour-specific alterations through analysis of three independent retrospective patient cohorts from two clinical centers, to derive a clinically useful signature. Design Quantitative comprehensive lipidomic analysis was performed by direct infusion electrospray ionization coupled to tandem mass spectrometry (ESI-MS/MS) and high-resolution mass spectrometry (HR-MS) on matched non-diseased mucosa and tumor tissue in a discovery cohort (n=106). Results were validated in two independent cohorts (n=28, and n=20), associated with genomic and clinical data, and lipidomic data from a genetic mouse tumor model (Apc1638N). Results Significant differences were found between tumor and normal tissue for glycero-, glycerophospho- and sphingolipids in the discovery cohort. Comparison to the validation collectives unveiled that glycerophospholipids showed high interpatient variation and were strongly affected by preanalytical conditions, whereas glycero- and sphingolipids appeared more robust. Signatures of sphingomyelin (SM) and triacylglycerol (TG) species significantly differentiated cancerous from non-diseased tissue in both validation studies. Moreover, lipogenic enzymes were significantly upregulated in CRC, and FASN gene expression was prognostically detrimental. The TG profile was significantly associated with post-operative disease-free survival and lymphovascular invasion, and was essentially conserved in murine digestive cancer, but not associated with microsatellite status, KRAS or BRAF mutations, or T-cell infiltration. Conclusion Analysis of the CRC lipidome revealed a robust TG-species signature with prognostic potential. A better understanding of the cancer-associated glycerolipid and sphingolipid metabolism may lead to novel therapeutic strategies.