Mutant IDH and non-mutant chondrosarcomas display distinct cellular metabolomes

Cancer & Metabolism

Hongyuan Zhang¹  John T. Martin¹  Benjamin A. Alman¹  Olga Ilkayeva²  Christopher B. Newgard²  Adrian Kwan Ho Loe³  Sinthu Pathmanapan⁴  Jay S. Wunder⁵  Guo-Fang Zhang⁶ 

[1] Department of Orthopaedic Surgery, Duke University, 311 Trent, 27710, Durham, NC, USA;Department of Pharmacology & Cancer Biology, Duke University, Durham, NC, USA;Sarah W. Stedman Nutrition and Metabolism Center and Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC, USA;Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, ON, Canada;Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, ON, Canada;Institute of Medical Science, University of Toronto, Toronto, ON, Canada;Lunenfeld-Tanenbaum Research Institute, and the University Musculoskeletal Oncology Unit, Mount Sinai Hospital, Toronto, ON, Canada;Sarah W. Stedman Nutrition and Metabolism Center and Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC, USA;

关键词: Chondrosarcoma;    Metabolism;    Mutant IDH;    Cancer;    Genetic mutation;    Amino acids;    Acylcarnitines;    TCA cycle;    Glycolysis;   

DOI  :  10.1186/s40170-021-00247-8

来源: Springer

【 摘 要 】

BackgroundMajority 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.MethodsHere, 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.ResultsUMAP 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.ConclusionsOverall, our findings suggest that IDH mutations induce global metabolic changes in chondrosarcomas and shed light on deranged metabolic pathways.

【 授权许可】

CC BY