@article{570ae77442824f98a3ec6778121101d8,
title = "Isotope tracing in adult zebrafish reveals alanine cycling between melanoma and liver",
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.",
keywords = "alanine cycle, cancer, cancer metabolism, isotope tracing, melanoma, metabolite exchange, metabolomics, zebrafish",
author = "Naser, {Fuad J.} and Jackstadt, {Madelyn M.} and Ronald Fowle-Grider and Spalding, {Jonathan L.} and Kevin Cho and Ethan Stancliffe and Doonan, {Steven R.} and Kramer, {Eva T.} and Lijun Yao and Bradley Krasnick and Li Ding and Fields, {Ryan C.} and Kaufman, {Charles K.} and Shriver, {Leah P.} and Johnson, {Stephen L.} and Patti, {Gary J.}",
note = "Funding Information: Financial support was received for this work from NIH awards R35ES028365 (G.J.P.), U01CA235482 (G.J.P.), and R24OD024624 (G.J.P.) as well as the Edward Mallinckrodt, Jr. Foundation (G.J.P.) and the Pew Charitable Trusts (G.J.P.). We dedicate this work to the late Stephen L. Johnson, who was an inspiring mentor to the co-authors. His collaborative generosity was essential to carrying out these studies. The authors thank Wandy Beatty of the Molecular Microbiology Imaging Facility for assistance with periodic acid-Schiff (PAS) imaging. F.J.N. M.M.J. and G.J.P. designed the study. F.J.N. M.M.J. R.F.-G. J.L.S. S.L.J. and G.J.P. contributed to the development of the zebrafish-metabolomics workflow. F.J.N. and M.M.J. performed all zebrafish experiments. F.J.N. M.M.J. and J.L.S. bred and maintained animals. K.C. and E.S. contributed to data processing and data analysis. S.R.D. performed tissue slicing. E.T.K. and C.K.K. performed expression analysis for zebrafish specimens. L.Y. B.K. L.D. and R.C.F. performed expression analysis for human melanoma. F.J.N. M.M.J. L.P.S. and G.J.P. wrote the manuscript. All authors discussed the results, contributed to data interpretation, and commented on the manuscript. G.J.P. is a scientific advisory board member for Cambridge Isotope Laboratories. Funding Information: Financial support was received for this work from NIH awards R35ES028365 (G.J.P.), U01CA235482 (G.J.P.), and R24OD024624 (G.J.P.) as well as the Edward Mallinckrodt, Jr. Foundation (G.J.P.) and the Pew Charitable Trusts (G.J.P.). We dedicate this work to the late Stephen L. Johnson, who was an inspiring mentor to the co-authors. His collaborative generosity was essential to carrying out these studies. The authors thank Wandy Beatty of the Molecular Microbiology Imaging Facility for assistance with periodic acid-Schiff (PAS) imaging. Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",
year = "2021",
month = jul,
day = "6",
doi = "10.1016/j.cmet.2021.04.014",
language = "English",
volume = "33",
pages = "1493--1504.e5",
journal = "Cell Metabolism",
issn = "1550-4131",
number = "7",
}