Pathmanapan Sinthu, Ilkayeva Olga, Martin John T, Loe Adrian Kwan Ho, Zhang Hongyuan, Zhang Guo-Fang, Newgard Christopher B, Wunder Jay S, Alman Benjamin A
Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, ON, Canada.
Institute of Medical Science, University of Toronto, Toronto, ON, Canada.
Cancer Metab. 2021 Mar 24;9(1):13. doi: 10.1186/s40170-021-00247-8.
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.
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.
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.
Overall, our findings suggest that IDH mutations induce global metabolic changes in chondrosarcomas and shed light on deranged metabolic pathways.
大多数软骨肉瘤与多种基因改变相关，包括异柠檬酸脱氢酶1（IDH1）和IDH2基因的体细胞突变，但这些突变酶对细胞代谢和肿瘤能量代谢的下游影响尚不清楚。由于IDH突变可能参与软骨肉瘤的恶性转化，我们旨在探索IDH突变型和非突变型软骨肉瘤的代谢组学变化。
在此，我们通过靶向质谱分析了17个患者来源的异种移植瘤中的69种以上代谢物，以确定突变型IDH1、突变型IDH2和非突变型软骨肉瘤中是否存在代谢组学差异。对我们的数据集进行了UMAP（均匀流形近似和投影）分析，以检查基于基因型的每个软骨肉瘤之间可能存在的潜在相似性。
UMAP显示，与非突变型软骨肉瘤相比，突变型IDH软骨肉瘤具有独特的代谢谱。更具体地说，我们的靶向代谢组学研究揭示了软骨肉瘤中三羧酸（TCA）循环的有机酸中间体、氨基酸和特定酰基肉碱的大规模差异。乳酸和TCA循环后期中间体在突变型IDH软骨肉瘤中升高，提示糖酵解代谢增加以及可能存在向TCA循环的回补流入。在突变型IDH软骨肉瘤中发现氨基酸广泛升高。一些不同碳链长度的酰基肉碱在突变型IDH软骨肉瘤中也升高，但根据肿瘤基因型的聚类最少。对先前发表的基因表达谱分析显示，突变型IDH软骨肉瘤中几个代谢基因的表达增加，这也与患者生存率相关。
总体而言，我们的研究结果表明，IDH突变在软骨肉瘤中诱导了整体代谢变化，并揭示了紊乱的代谢途径。
