PUBLICATION

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

Authors
Naser, F.J., Jackstadt, M.M., Fowle-Grider, R., Spalding, J.L., Cho, K., Stancliffe, E., Doonan, S.R., Kramer, E.T., Yao, L., Krasnick, B., Ding, L., Fields, R.C., Kaufman, C.K., Shriver, L.P., Johnson, S.L., Patti, G.J.
ID
ZDB-PUB-210515-16
Date
2021
Source
Cell Metabolism   33(7): 1493-1504.e5 (Journal)
Registered Authors
Johnson, Stephen L.
Keywords
alanine cycle, cancer, cancer metabolism, isotope tracing, melanoma, metabolite exchange, metabolomics, zebrafish
MeSH Terms
  • Aging/pathology
  • Alanine/metabolism*
  • Animals
  • Animals, Genetically Modified
  • Cell Tracking/methods
  • Disease Models, Animal
  • Gluconeogenesis/genetics
  • Humans
  • Isotope Labeling/methods
  • Liver/metabolism*
  • Liver/pathology
  • Liver Neoplasms/genetics
  • Liver Neoplasms/metabolism
  • Liver Neoplasms/pathology
  • Melanoma/genetics
  • Melanoma/metabolism*
  • Melanoma/pathology
  • Metabolomics
  • Zebrafish
PubMed
33989520 Full text @ Cell Metab.
Abstract
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.
Genes / Markers
Figures
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping