Extended Data Fig. 3: Glucose-derived labelling of tissue and plasma metabolites in patients and mice with brain tumours.
From: Rewiring of cortical glucose metabolism fuels human brain cancer growth
a, Time course of m + 3 lactate in plasma from 8 patients infused with [U13C]glucose. Plasma from patient 8 could not be analysed at time 0. b, Time course of m + 3 lactate in plasma from orthotopic GBM38 bearing mice (3–10 per timepoint) infused with [U13C]glucose. Data are mean ± s.d. at each timepoint. c, Schema of glucose carbon (red circles) redistribution into glycolytic intermediates. Scrambling can occur via recombination with unlabelled intermediates in the pentose phosphate cycle (E4P, S7P, R5P, GAP). d, Normalized enrichment of m + 6 UDP-glucose in intracranial tissues from 8 glioma patients infused with [U13C]glucose. e, Normalized enrichment of m + 6 UDP-glucose enrichment in cortex and orthotopic GBM tissue isolated from intracranial tumour-bearing mice infused with [U13C]glucose. f, Schema of 13C-labelling in TCA cycle intermediates and neurotransmitters arising from m + 3 pyruvate. Red circles indicate entry through pyruvate dehydrogenase, and gold circles indicate entry through pyruvate carboxylase. Blue circles indicate labelling patterns possible on second TCA cycle turn. g-i, Isotopologue abundance levels of citrate (g), succinate (h), and malate (i) in cortex and GBM tissues at indicated time points from orthotopic GBM38-bearing mice infused with [U13C]glucose. j-l, Percent change in citrate (j), succinate (k), and malate (l) isotopologues from 120 to 240 min in mice infused with [U13C]-glucose. m, Schema of purine synthetic pathways. Green and yellow circles indicate glycine- and folate-derived carbons, respectively. Blue circles indicate R5P-derived carbons. Partial shading of these circles indicates that a variety of labelling patterns are possible. n, Normalized enrichment of R5P in intracranial tissues from 8 glioma patients infused with [U13C]glucose. o, Normalized enrichment of R5P in cortex and orthotopic GBM tissue isolated from intracranial tumour-bearing mice infused with [U13C]glucose. p-v, Normalized enrichment of IMP (p), inosine (q), AMP (r), ADP (s), GMP (t), GDP (u), and guanosine (v) in intracranial tissues from glioma patients infused with [U13C]glucose. w, Schema of pyrimidine synthetic pathways. Magenta indicates aspartate-derived carbons, blue indicates R5P-derived carbons, and yellow indicates folate-derived carbons. Partial shading is used to indicate that a variety of labelling patterns are possible. x,y, Normalized enrichment of UMP (x) and dTDP (y) in intracranial tissues from glioma patients infused with [U13C]glucose. z, Schematic of carbon incorporation into NAD and NADH. In d, e, n, and o, data are mean ± s.d. of metabolite enrichments normalized to labelled plasma glucose on a per-patient or per-mouse basis. Comparisons between groups were performed using linear mixed-effects models with a random intercept for individual, and multiple pairwise comparisons across tissue types were adjusted using Holm’s method. All statistical tests were two-sided. For mice, n = 4–16 samples per group were from 16 mice (4–7 mice for each orthotopic model with cortex samples from all mice pooled) were analysed. For humans, n = 7–8 samples per group were analysed. Some metabolites were not reliably detected in every tissue sample and were therefore not shown. In g, h, and i, data are mean ± s.d. of n = 3–9 samples from 1–3 mice per timepoint. In j, k, and l, data are mean ± s.d. Error bars are propagated from uncertainty in t = 120 and t = 240 min datapoints. n = 9 samples from 3 mice per time point. In c, f, m, w, and z, some intermediates are omitted from pathway diagrams for conciseness. Abbreviations: G6P (glucose 6-phosphate), F6P (fructose 6-phosphate), DHAP (dihydroxyacetone phosphate), GAP (glyceraldehyde 3-phosphate), 3PG (3-phosphoglycerate), R5P (ribose 5-phosphate), E4P (erythrose 4-phosphate), S7P (sedoheptulose 7-phosphate), PRPP (phosphoribosyl pyrophosphate), Me-THF (N10-formyltetrahydrofolate), 5,10-MeTHF (5,10-methylenetetrahydrofolate), NAM (nicotinamide).
