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 13 C-glucose infusions. Pediatric tumors differ from adult cancers in their low mutational burden and derivation from embryonic tissues. Here, we used 13 C 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-13 C]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 mixedeffect analyses. Findings: We studied 23 tumors from 22 patients. All of the tumors analyzed by [U-13 C]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 [U 13 C]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.

Comprehensive Metabolic Profiling of MYC-Amplified Medulloblastoma Tumors Reveals Key Dependencies on Amino Acid, Tricarboxylic Acid and Hexosamine Pathways

“…Multiple drugs are in development in other tumors that target the urea cycle through inhibition of aspartate or ASS1 [ 72 , 73 ], and some of these agents could be applied to medulloblastoma tumors with vulnerable metabolic profiles. Recent publications suggest that clinical metabolic profiling can be performed on pediatric primary tumor samples, suggesting that targeting metabolic profiles could be a new frontier in pediatric cancer and in brain tumors in general [ 74 ].…”

Cell energy metabolism and bone formation

“…Using the same approach of stable-isotope tracing in culture, in vivo flux analysis differs by the fact of requiring intravenous infusion of 13 C and later tissue collection. There are no established protocols for 13 C infusion regimen targeting bone tissue but, intra-operative 13 C-glucose infusions in humans subjects showed sufficient tracing resolution in osteosarcoma samples ( Johnston et al, 2021 ). This suggests that in vivo flux analysis can potentially be used to perform metabolic tracing in bone tissue, having an important applicability in understanding how different mouse models and signaling manipulations can impact bone metabolism ( Sanchez-Arago et al, 2013 ; Lee et al, 2019 ; Hollenberg et al, 2020 ; Pattappa et al, 2011 ; Forni et al, 2016 ).…”

Impact of cancer metabolism on therapy resistance – Clinical implications

“…Infusion of [U-13 C]glucose in patients revealed distinct metabolic fates depending on the tumor type. A recent study has reported that pediatric solid tumors use both glycolysis and the TCA cycle in vivo, with subtype-specific differences observed in glucose handling (Johnston et al, 2021).…”