Mutant IDH and non-mutant chondrosarcomas display distinct cellular metabolomes

Abstract

Background: Majority of chondrosarcomas are associated with a number of genetic alterations, including somatic mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 genes, but the downstream effects of these mutated enzymes on cellular metabolism and tumor energetics are unknown. As IDH mutations are likely to be involved in malignant transformation of chondrosarcomas, we aimed to exploit metabolomic changes in IDH mutant and non-mutant chondrosarcomas.

Methods: Here, we profiled over 69 metabolites in 17 patient-derived xenografts by targeted mass spectrometry to determine if metabolomic differences exist in mutant IDH1, mutant IDH2, and non-mutant chondrosarcomas. UMAP (Uniform Manifold Approximation and Projection) analysis was performed on our dataset to examine potential similarities that may exist between each chondrosarcoma based on genotype.

Results: UMAP revealed that mutant IDH chondrosarcomas possess a distinct metabolic profile compared with non-mutant chondrosarcomas. More specifically, our targeted metabolomics study revealed large-scale differences in organic acid intermediates of the tricarboxylic acid (TCA) cycle, amino acids, and specific acylcarnitines in chondrosarcomas. Lactate and late TCA cycle intermediates were elevated in mutant IDH chondrosarcomas, suggestive of increased glycolytic metabolism and possible anaplerotic influx to the TCA cycle. A broad elevation of amino acids was found in mutant IDH chondrosarcomas. A few acylcarnitines of varying carbon chain lengths were also elevated in mutant IDH chondrosarcomas, but with minimal clustering in accordance with tumor genotype. Analysis of previously published gene expression profiling revealed increased expression of several metabolism genes in mutant IDH chondrosarcomas, which also correlated to patient survival.

Conclusions: Overall, our findings suggest that IDH mutations induce global metabolic changes in chondrosarcomas and shed light on deranged metabolic pathways.

Keywords: Acylcarnitines; Amino acids; Cancer; Chondrosarcoma; Genetic mutation; Glycolysis; Metabolism; Mutant IDH; TCA cycle.

Fig. 1

Organic acid quantification of non-mutant, mutant IDH1, and mutant IDH2 chondrosarcoma tissue by gas chromatography/mass spectrometry (GC/MS). Quantification of glycolytic a pyruvate, b lactate and TCA cycle metabolites c citrate, d ⍺-ketoglutarate, e succinate, f fumarate, g malate, of non-mutant, mutant IDH1, and mutant IDH2 chondrosarcoma tissue. p-value = Student’s t-test p < 0.05, *: significant p-value

Fig. 2

Amino acid profiles of non-mutant, mutant IDH, and mutant IDH2 chondrosarcoma tissue quantified by mass spectrometry (MS/MS) display a global elevation in mutant IDH chondrosarcomas. Radar profiles of a non-mutant chondrosarcomas, b mutant IDH1 chondrosarcomas, c mutant IDH2 chondrosarcomas, d scatter plot of amino acids in each genotype of chondrosarcoma. p-value = Student’s t-test p < 0.05, *: significant p-value

Fig. 3

Acylcarnitine profiles of non-mutant, mutant IDH1, and mutant IDH2 chondrosarcoma tissues, quantified by mass spectrometry (MS/MS) display an elevation of species in mutant IDH chondrosarcomas. Acylcarnitines classified according to increasing carbon chain length: a short-chain acylcarnitines, b medium-chain acylcarnitines, c long-chain acylcarnitines, d very-long-chain acylcarnitines. p-value = Student’s t-test p < 0.05, *: significant p-value