Spatiotemporal metabolic networks in a preclinical model of pancreatic cancer and associated cachexia

Cachexia or body wasting is a significant contributing factor to the morbidity and mortality of pancreatic cancer. Despite an unmet need, its metabolic underpinnings remain poorly understood. Here, we characterize a mouse model that recaptures the longitudinal progression of human cachexia during pancreatic cancer development. We profile the metabolomes of pre-, early- and late-stage cancer-associated cachexia in male and female pancreas, its interstitial fluid (IF), plasma, liver, adipose tissue and skeletal muscle. We find that each tissue has a unique metabolome and trajectory across stages and reveal a marked lipid enrichment in the tumor IF. Using mathematical modeling, we identify metabolites participating in cross-tissue networks and in vivo validate a lactate-glucose conversion. We find systemic metabolic changes prior to weight loss and use feature selection algorithms to identify early detection markers. Our study provides a resource for system-wide metabolic evolution of pancreatic cancer and associated cachexia, highlighting the potential for timely diagnostics and interventions. Cachexia commonly develops in patients with pancreatic cancer and is closely linked to increased morbidity and mortality. Here, the authors provide an in-depth longitudinal characterization of systemic metabolomic alterations in a mouse model of pancreatic cancer–associated cachexia.