The cachexia lipidome - a novel role of modified ceramides in cancer

8th Munich Metabolomics Symposium
Applications of clinical metabolomics in oncology and cardiovascular diseases
Virtual event November 12th, 2021
Part 1 - Oncology & Immunology

Organized by Helmholtz Zentrum Munich, Technical University Munich, and biocrates

Dr. Maria Rohm
Institute for Diabetes and Cancer, Helmholtz Zentrum Munich, Germany

Abstract:
Cancer cachexia (CCx) is a multifactorial energy‐wasting syndrome reducing the efficiency of anti‐cancer therapies, quality of life, and survival of cancer patients. Despite the prominent role of disturbed lipid metabolism in CCx, studies addressing the role of bioreactive circulating lipids in CCx are currently missing. By performing a broad range lipid analysis of plasma from well‐established CCx mouse models as well as cachectic and weight stable cancer patients, we aimed at characterizing circulating lipids characteristic for CCx. Using the Lipidyzer™ platform, we detected 13 lipid classes and more than 1100 lipid species. A decrease in several lysophosphatidylcholine (LPC) species and an increase in numerous sphingolipids including sphingomyelins (SMs), ceramides (CERs), hexosyl‐ceramides (HCERs) and lactosyl‐ceramides (LCERs), were mutual features of CCx in both mice and cancer patients. Notably, sphingolipid levels gradually increased during cachexia development. Key enzymes involved in ceramide synthesis were elevated in liver but not in adipose, muscle, or tumor tissues, suggesting that ceramide turnover in the liver is a major contributor to elevated sphingolipid levels in CCx. LPC(16:1), LPC(20:3), SM(16:0), SM(24:1), CER(16:0), CER(24:1), HCER(16:0), and HCER(24:1) were the most consistently affected lipid species between mice and humans and correlated with the severity of body weight loss. In conclusion, high levels of sphingolipids, specifically ceramides and modified ceramides, are a defining feature of murine and human CCx and may contribute to tissue wasting and skeletal muscle atrophy through the inhibition of anabolic signals. The progressive increase in sphingolipids during cachexia development supports their potential as early biomarkers for CCx.