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Ecker, J.* ; Benedetti, E.* ; Kindt, A. ; Höring, M.* ; Perl, M.* ; Machmüller, A.C. ; Sichler, A.* ; Plagge, J.* ; Wang, Y.* ; Zeissig, S.* ; Shevchenko, A.* ; Burkhardt, R.* ; Krumsiek, J.* ; Liebisch, G.* ; Janssen, K.P.*

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

Gastroenterology 161, 910-923.e19 (2021)
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Open Access Green as soon as Postprint is submitted to ZB.
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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Biomarker ; Mass Spectrometry ; Signature ; Sphingomyelin ; Triacylglycerol; Tandem Mass-spectrometry; High-throughput Quantification; Polyunsaturated Fatty-acids; Hilic-hplc/esi-ms; Metabolism; Risk; Phosphatidylcholine; Differentiation; Sphingomyelin; Extraction
ISSN (print) / ISBN 0016-5085
e-ISSN 1528-0012
Quellenangaben Volume: 161, Issue: 3, Pages: 910-923.e19 Article Number: , Supplement: ,
Publisher Elsevier
Publishing Place 1600 John F Kennedy Boulevard, Ste 1800, Philadelphia, Pa 19103-2899 Usa
Reviewing status Peer reviewed
Grants Deutsche Forschungsgemeinschaft