Mutant IDH and non-mutant chondrosarcomas display distinct cellular metabolomes.
Mutant IDH and non-mutant chondrosarcomas display distinct cellular metabolomes.
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突变型IDH和非突变型软骨肉瘤表现出不同的细胞代谢组。
DOI：
10.1186/s40170-021-00247-8
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发表时间：
2021-03-24
影响因子：
5.9
通讯作者：
Alman BA
中科院分区：
文献类型：
--
作者：
Pathmanapan S;Ilkayeva O;Martin JT;Loe AKH;Zhang H;Zhang GF;Newgard CB;Wunder JS;Alman BA
大多数软骨肉瘤与许多基因改变有关，包括异柠檬酸脱氢酶1(IDH1)和IDH2基因的体细胞突变，但这些突变的酶对细胞代谢和肿瘤能量学的下游影响尚不清楚。由于IDH突变可能与软骨肉瘤的恶变有关，我们的目标是利用IDH突变和非突变软骨肉瘤的代谢变化。在这里，我们通过靶向质谱学分析了17例患者来源的异种移植瘤中的69种代谢物，以确定突变的IDH1、突变的IDH2和非突变的软骨肉瘤是否存在代谢组学上的差异。在我们的数据集上进行了UMAP(统一流形近似和投影)分析，以检查基于基因的每个软骨肉瘤之间可能存在的潜在相似性。UMAP显示突变的IDH软骨肉瘤与非突变的软骨肉瘤相比具有不同的代谢特征。更具体地说，我们的目标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、氨基酸和特定的酰卡尼汀之间的大规模差异。在突变的IDH软骨肉瘤中，乳酸盐和TCA循环晚期中间产物升高，提示糖酵解代谢增加，可能有促性腺激素进入TCA循环。在突变的IDH软骨肉瘤中发现了氨基酸的广泛升高。在突变的IDH软骨肉瘤中，几种不同碳链长度的酰肉碱也升高，但根据肿瘤基因的不同有最小的聚集。对先前发表的基因表达谱的分析显示，在突变的IDH软骨肉瘤中，几个代谢基因的表达增加，这也与患者的生存相关。总体而言，我们的发现表明IDH突变导致软骨肉瘤的全球代谢变化，并阐明了错乱的代谢途径。网上版载有补充材料，可在10.1186/s4017021-00247-8查阅。
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. The online version contains supplementary material available at 10.1186/s40170-021-00247-8.
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影响因子：
29
作者：
Kimmelman AC;White E
通讯作者：
White E
影响因子：
4.5
作者：
Ferrara CT;Wang P;Neto EC;Stevens RD;Bain JR;Wenner BR;Ilkayeva OR;Keller MP;Blasiole DA;Kendziorski C;Yandell BS;Newgard CB;Attie AD
通讯作者：
Attie AD
影响因子：
78.5
作者：
Mathew, Robin;Karantza-Wadsworth, Vassiliki;White, Eileen
通讯作者：
White, Eileen
影响因子：
8.8
作者：
Badur MG;Muthusamy T;Parker SJ;Ma S;McBrayer SK;Cordes T;Magana JH;Guan KL;Metallo CM
通讯作者：
Metallo CM
DOI：
10.1073/pnas.1424400112
发表时间：
2015-03-03
影响因子：
11.1
作者：
Hirata, Makoto;Sasaki, Masato;Alman, Benjamin A.
通讯作者：
Alman, Benjamin A.