Pauline Morigny, Honglei Ji, Laura Cussonneau, Sabrina Zorzato, 권윤, Fabien Riols, Doris Kaltenecker, Alisa Maier, Vignesh Karthikaisamy, Samantha Corrà, Tanja Krauss, Claudine Seeliger, Syed Qaaifah Gillani, Joël J. Tissink, Sandra Lacas‐Gervais, Tuna Felix Samanci, Adriano Maida, Raul Terrón-Expósito, Angela Trinca, Christine von Toerne, Leonardo Nogara, Melina Claussnitzer, Olga Prokopchuk, Jeannine Bachmann, M Berriel Diaz, Laure B. Bindels, Ondřej Kuda, H Hauner, Mark Haid, Stephan Herzig, Carlo Viscomi, Jérôme Gilleron, Anja Zeigerer, Bert Blaauw, Maria Rohm
Cachexia is a metabolic wasting syndrome affecting many patients with cancer, with poor survival outcomes. Disturbed lipid metabolism is a hallmark of cachexia, and our previous work has identified increased levels of circulating ceramides, which are bioactive lipids with adverse effects in metabolic diseases, as biomarkers for cachexia in mouse models and patients. Here, we investigated the role of ceramides on cachexia development using the well-established C26 colon carcinoma model. We demonstrated that elevated ceramides in cachexia arose from increased liver synthesis. We showed that ceramides directly contributed to impaired mitochondrial function and energy homeostasis in cachexia target tissues. Targeting ceramide synthesis using miRNA interference, or myriocin, an approved compound targeting the key synthesis enzyme serine palmitoyltransferase (SPT), improved markers of muscle atrophy in cachectic male mice. Importantly, we demonstrated that key enzymes involved in ceramide production were also elevated in livers, but not in other organs, of patients with cancer cachexia, correlating with disease severity. Our data place ceramides as contributors to metabolic dysfunction in cachexia and highlight the suitability of the ceramide synthesis pathway for therapeutic targeting.