Isotope tracing in adult zebrafish reveals alanine cycling between melanoma and liver

The cell-intrinsic nature of tumor metabolism has become increasingly well characterized. The impact that tumors have on systemic metabolism, however, has received less attention. Here, we used adult zebrafish harboring BRAFV600E-driven melanoma to study the effect of cancer on distant tissues. By applying metabolomics and isotope tracing, we found that melanoma consume ~15 times more glucose than other tissues measured. Despite this burden, circulating glucose levels were maintained in disease animals by a tumor-liver alanine cycle. Excretion of glucose-derived alanine from tumors provided a source of carbon for hepatic gluconeogenesis and allowed tumors to remove excess nitrogen from branched-chain amino acid catabolism, which we found to be activated in zebrafish and human melanoma. Pharmacological inhibition of the tumor-liver alanine cycle in zebrafish reduced tumor burden. Our findings underscore the significance of metabolic crosstalk between tumors and distant tissues and establish the adult zebrafish as an attractive model to study such processes. [Display omitted] •Adult zebrafish are well suited for steady-state labeling and metabolomics•Branched-chain amino acid catabolism by melanoma contributes to alanine excretion•Glucose-derived alanine excreted from the tumor is used for hepatic gluconeogenesis•Pharmacological inhibition of the tumor-liver alanine cycle reduces tumor burden Using a workflow they established for isotope tracing in adult zebrafish, Naser et al. provide evidence that non-malignant tissues alter their metabolism to support tumor growth. They demonstrate that glucose-derived alanine is excreted from melanoma and transferred to the liver for gluconeogenesis. Pharmacologically impairing this metabolite exchange decreases tumor burden.