Mutant IDH regulates glycogen metabolism from early cartilage development to malignant chondrosarcoma formation

作者：Sinthu Pathmanapan, Raymond W.M. Poon, Tomasa Barrientos De Renshaw, Puviindran Nadesan, Makoto Nakagawa, Gireesh Seesankar, Adrian Kwan Ho Loe, Hongyuan H. Zhang, Joan J. Guinovart, Jordi Durán, Christopher B. Newgard, Jay Steven Wunder, Benjamin Aaron Alman · 发表于：Cell Reports · 年份：2023 · DOI：10.1016/j.celrep.2023.112578 · 被引用次数：18 · 研究领域：Bone Tumor Diagnosis and Treatments、Sarcoma Diagnosis and Treatment、Cancer-related molecular mechanisms research

Chondrosarcomas are the most common malignancy of cartilage and are associated with somatic mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 genes. Somatic IDH mutations are also found in its benign precursor lesion, enchondromas, suggesting that IDH mutations are early events in malignant transformation. Human mutant IDH chondrosarcomas and mutant Idh mice that develop enchondromas investigated in our studies display glycogen deposition exclusively in mutant cells from IDH mutant chondrosarcomas and Idh1 mutant murine growth plates. Pharmacologic blockade of glycogen utilization induces changes in tumor cell behavior, downstream energetic pathways, and tumor burden in vitro and in vivo. Mutant IDH1 interacts with hypoxia-inducible factor 1α (HIF1α) to regulate expression of key enzymes in glycogen metabolism. Here, we show a critical role for glycogen in enchondromas and chondrosarcomas, which is likely mediated through an interaction with mutant IDH1 and HIF1α.