Cachexia is a wasting disorder associated with high morbidity and mortality in patients with cancer. Tumour-host interaction and maladaptive metabolic reprogramming are substantial, yet poorly understood, contributors to cachexia. Here we present a comprehensive overview of the spatio-temporal metabolic reprogramming during cachexia, using integrated metabolomics, RNA sequencing and 13C-glucose tracing data from multiple tissues and tumours of C26 tumour-bearing male mice at different disease stages. We identified one-carbon metabolism as a tissue-overarching pathway characteristic for metabolic wasting in mice and patients and linked to inflammation, glucose hypermetabolism and atrophy in muscle. The same metabolic rewiring also occurred in five additional mouse models, namely Panc02, 8025, ApcMin, LLC and KPP, and a humanised cachexia mouse model. Together, our study provides a molecular framework for understanding metabolic reprogramming and the multi-tissue metabolite-coordinated response during cancer cachexia progression, with one-carbon metabolism as a tissue-overarching mechanism linked to wasting.

BioTechMed Graz Graz Austria

Chair Molecular Metabolic Control Technical University Munich Munich Germany

Computational Discovery Research Institute for Diabetes and Obesity Helmholtz Center Munich Neuherberg Germany

Department of Medicine Harvard Medical School Boston MA USA

Department of Surgery Klinikum rechts der Isar School of Medicine Technical University of Munich Munich Germany

Diabetes Unit and Center for Genomic Medicine Massachusetts General Hospital Boston MA USA

Else Kröner Fresenius Center for Nutritional Medicine School of Life Sciences Technical University of Munich Freising Weihenstephan Germany

German Center for Cardiovascular Research partner site Munich Heart Alliance Munich Germany

German Center for Diabetes Research Munich Germany

Institute for Diabetes and Cancer Helmholtz Center Munich Neuherberg Germany

Institute of Molecular Biosciences University of Graz Graz Austria

Institute of Nutritional Medicine School of Medicine Technical University of Munich Munich Germany

Joint Heidelberg IDC Translational Diabetes Program Inner Medicine 1 University Hospital Heidelberg Germany

Metabolism and Nutrition Research Group Louvain Drug Research Institute UCLouvain Université catholique de Louvain Brussels Belgium

Metabolism of Bioactive Lipids Institute of Physiology of the Czech Academy of Sciences Prague Czech Republic

The Novo Nordisk Foundation Center for Genomic Mechanisms of Disease Broad Institute of MIT and Harvard Cambridge MA USA

Welbio Department WEL Research Institute Wavre Belgium

ZIEL Institute for Food and Health Technical University of Munich Freising Weihenstephan Germany

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