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 BRAF(V600E)-driven melanoma to study the effect of cancer on distant tissues. By applying metabolomics and isotope tracing, we found that melanoma consume similar to 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.

Automated summary

The study revealed that melanoma consumes significantly more glucose than other tissues and the tumor liver alanine cycle plays a crucial role in maintaining circulating glucose levels in diseased animals. Inhibition of this cycle reduced tumor burden, highlighting the importance of metabolic crosstalk between tumors and distant tissues.