@article{381db71459c443ff8527426a00ad9a98,
title = "Isotope tracing reveals glycolysis and oxidative metabolism in childhood tumors of multiple histologies",
abstract = "Background: Survival among children with high-risk solid tumors remains poor. Reprogrammed metabolism promotes tumor growth and may contain therapeutic liabilities. Tumor metabolism has been assessed in adults using intra-operative 13C-glucose infusions. Pediatric tumors differ from adult cancers in their low mutational burden and derivation from embryonic tissues. Here, we used 13C infusions to examine tumor metabolism in children, comparing phenotypes among tumor types and between childhood and adult cancers. Methods: Patients recruited to the clinical trial NCT03686566 received an intra-operative infusion of [U-13C]glucose during tumor resection to evaluate central carbon pathways in the tumor, with concurrent metabolomics to provide a broad overview of metabolism. Differential characteristics were determined using multiple comparison tests and mixed-effect analyses. Findings: We studied 23 tumors from 22 patients. All of the tumors analyzed by [U-13C]glucose contained labeling in glycolytic and tricarboxylic acid (TCA) cycle intermediates. Labeling in the TCA cycle indicated the activity of pyruvate dehydrogenase (PDH) and pyruvate carboxylase (PC), with PDH predominating. Neuroblastomas had high lactate labeling relative to other childhood cancers and lung cancer and were distinguished by abundant tyrosine catabolites consistent with catecholamine synthesis. Conclusions: Intra-operative [U13C]glucose infusions are safe and informative in pediatric cancer. Tumors of various histologies use glycolysis and oxidative metabolism, with subtype-selective differences evident from this small cohort. Expanding this cohort may uncover predictive biomarkers and therapeutic targets from tumor metabolism. Funding: National Cancer Institute (NCI) grants to P.L. ( R21CA220090-01A1), R.J.D. ( R35CA22044901), and B.F. ( K99CA237724); Howard Hughes Medical Institute (HHMI), the 1 Million 4 Anna Foundation, and the Robert L. Moody Sr. Faculty Scholar Award funding to R.J.D.; Children's Clinical Research Advisory Committee funding to K.J.; and Leopoldina Fellowship ( LPDS 2016-16) from the German National Academy of Sciences and Fritz Thyssen Foundation funding to A.T.",
keywords = "Translation to Humans, cancer, glucose, isotopes, metabolism, metabolomics, neuroblastoma, pediatrics, sarcoma",
author = "Kendra Johnston and Panayotis Pachnis and Alpaslan Tasdogan and Brandon Faubert and Zacharias, {Lauren G.} and Vu, {Hieu Sy} and Laurie Rodgers-Augustyniak and Allison Johnson and Fang Huang and Sean Ricciardo and Zhiyu Zhao and Mathews, {Thomas P.} and Tanya Watt and Patrick Leavey and DeBerardinis, {Ralph J.}",
note = "Funding Information: We thank all of the patients who participated in the study and their families. We also thank our colleagues in general surgery, orthopedic surgery, interventional radiology, and investigational pharmacy. Jessica Sudderth provided assistance in the isotope enrichment measurements and feedback on the manuscript. Funding was provided by National Cancer Institute (NCI) grants to P.L. ( R21CA220090-01A1 ), R.J.D. ( R35CA22044901 ), and B.F. ( K99CA237724 ); Howard Hughes Medical Institute (HHMI), the 1 Million 4 Anna Foundation , and the Robert L. Moody Sr. Faculty Scholar Award funding to R.J.D.; Children{\textquoteright}s Clinical Research Advisory Committee funding to K.J.; and Leopoldina Fellowship ( LPDS 2016-16 ) from the German National Academy of Sciences and Fritz Thyssen Foundation funding to A.T . Funding Information: National Cancer Institute (NCI) grants to P.L. (R21CA220090-01A1), R.J.D. (R35CA22044901), and B.F. (K99CA237724); Howard Hughes Medical Institute (HHMI), the 1 Million 4 Anna Foundation, and the Robert L. Moody Sr. Faculty Scholar Award funding to R.J.D.; Children's Clinical Research Advisory Committee funding to K.J.; and Leopoldina Fellowship (LPDS 2016-16) from the German National Academy of Sciences and Fritz Thyssen Foundation funding to A.T.We thank all of the patients who participated in the study and their families. We also thank our colleagues in general surgery, orthopedic surgery, interventional radiology, and investigational pharmacy. Jessica Sudderth provided assistance in the isotope enrichment measurements and feedback on the manuscript. Funding was provided by National Cancer Institute (NCI) grants to P.L. (R21CA220090-01A1), R.J.D. (R35CA22044901), and B.F. (K99CA237724); Howard Hughes Medical Institute (HHMI), the 1 Million 4 Anna Foundation, and the Robert L. Moody Sr. Faculty Scholar Award funding to R.J.D.; Children's Clinical Research Advisory Committee funding to K.J.; and Leopoldina Fellowship (LPDS 2016-16) from the German National Academy of Sciences and Fritz Thyssen Foundation funding to A.T. K.J. T.W. P.L. and R.J.D. conceived of the project. K.J. L.R.-A. and A.J. managed the clinical protocol and consented and infused patients. K.J. P.P. and B.F. collected tumor samples from the infused patients. L.G.Z. H.S.V. K.J. and T.P.M. acquired metabolomics data. K.J. A.T. P.P. B.F. and R.J.D. processed, analyzed, and interpreted the data from the [U-13C]glucose infusions. F.H. analyzed the gene expression data. A.T. and P.P. performed the western blots. P.P. performed the mouse infusions. S.R. analyzed histopathological specimens. Z.Z. performed the statistical analysis. K.J. and R.J.D. wrote the manuscript. R.J.D. is an advisor for Agios Pharmaceuticals and Vida Ventures. Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",
year = "2021",
month = apr,
day = "9",
doi = "10.1016/j.medj.2021.01.002",
language = "English (US)",
volume = "2",
pages = "395--410.e4",
journal = "Med",
issn = "2666-6359",
publisher = "Cell Press",
number = "4",
}