Josef Ecker1, Elisa Benedetti2, Alida S D Kindt3, Marcus Höring4, Markus Perl5, Andrea Christel Machmüller6, Anna Sichler5, Johannes Plagge7, Yuting Wang8, Sebastian Zeissig8, Andrej Shevchenko9, Ralph Burkhardt4, Jan Krumsiek2, Gerhard Liebisch10, Klaus-Peter Janssen11. 1. ZIEL-Institute for Food & Health, Research Group Lipid Metabolism, Technical University of Munich, Freising, Germany. Electronic address: josef.ecker@tum.de. 2. Institute of Computational Biomedicine, Department of Physiology and Biophysics, Weill Cornell Medical College, New York, New York. 3. Division of Analytical Biosciences, Leiden Academic Centre for Drug Research, Leiden University, Leiden, the Netherlands; Institute of Computational Biology, Helmholtz Zentrum München, Neuherberg, Germany. 4. Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Regensburg, Regensburg, Germany. 5. Technical University of Munich, School of Medicine, Klinikum rechts der Isar, Department of Surgery, Munich, Germany. 6. Technical University of Munich, School of Medicine, Klinikum rechts der Isar, Department of Surgery, Munich, Germany; Institute for Diabetes and Obesity, Helmholtz Center Munich, Neuherberg, Germany. 7. ZIEL-Institute for Food & Health, Research Group Lipid Metabolism, Technical University of Munich, Freising, Germany. 8. Center for Regenerative Therapies Dresden, Technische Universität Dresden, Dresden, Germany; Department of Medicine I, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany. 9. Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany. 10. Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Regensburg, Regensburg, Germany. Electronic address: gerhard.liebisch@ukr.de. 11. Technical University of Munich, School of Medicine, Klinikum rechts der Isar, Department of Surgery, Munich, Germany. Electronic address: Klaus-Peter.Janssen@tum.de.
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 tumor-specific alterations through analysis of 3 independent retrospective patient cohorts from 2 clinical centers, to derive a clinically useful signature. DESIGN: Quantitative comprehensive lipidomic analysis was performed using direct infusion electrospray ionization coupled with tandem mass spectrometry (ESI-MS/MS) and high-resolution mass spectrometry (HR-MS) on matched nondiseased mucosa and tumor tissue in a discovery cohort (n = 106). Results were validated in 2 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 and triacylglycerol (TG) species significantly differentiated cancerous from nondiseased tissue in both validation studies. Moreover, lipogenic enzymes were significantly up-regulated in CRC, and FASN gene expression was prognostically detrimental. The TG profile was significantly associated with postoperative 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.
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 tumor-specific alterations through analysis of 3 independent retrospective patient cohorts from 2 clinical centers, to derive a clinically useful signature. DESIGN: Quantitative comprehensive lipidomic analysis was performed using direct infusion electrospray ionization coupled with tandem mass spectrometry (ESI-MS/MS) and high-resolution mass spectrometry (HR-MS) on matched nondiseased mucosa and tumor tissue in a discovery cohort (n = 106). Results were validated in 2 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 and triacylglycerol (TG) species significantly differentiated cancerous from nondiseased tissue in both validation studies. Moreover, lipogenic enzymes were significantly up-regulated in CRC, and FASN gene expression was prognostically detrimental. The TG profile was significantly associated with postoperative 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.
Authors: Khadija El-Hindi; Sebastian Brachtendorf; Jennifer Christina Hartel; Stephanie Oertel; Kerstin Birod; Nadine Merz; Sandra Trautmann; Dominique Thomas; Andreas Weigert; Tim J Schäufele; Klaus Scholich; Susanne Schiffmann; Thomas Ulshöfer; Olaf Utermöhlen; Sabine Grösch Journal: Int J Mol Sci Date: 2022-02-07 Impact factor: 5.923
Authors: Christine Dawczynski; Johannes Plagge; Gerhard Jahreis; Gerhard Liebisch; Marcus Höring; Claudine Seeliger; Josef Ecker Journal: Nutrients Date: 2022-07-26 Impact factor: 6.706
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