| Title: |
Mutant IDHregulates glycogen metabolism from early cartilage development to malignant chondrosarcoma formation |
| Authors: |
Pathmanapan, Sinthu, Poon, Raymond, De Renshaw, Tomasa Barrientos, Nadesan, Puviindran, Nakagawa, Makoto, Seesankar, Gireesh A., Ho Loe, Adrian Kwan, Zhang, Hongyuan H., Guinovart, Joan J., Duran, Jordi, Newgard, Christopher B., Wunder, Jay S., Alman, Benjamin A. |
| Source: |
Cell Reports; 20230101, Issue: Preprints |
| Abstract: |
Chondrosarcomas are the most common malignancy of cartilage and are associated with somatic mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2genes. Somatic IDHmutations are also found in its benign precursor lesion, enchondromas, suggesting that IDHmutations are early events in malignant transformation. Human mutant IDHchondrosarcomas and mutant Idhmice that develop enchondromas investigated in our studies display glycogen deposition exclusively in mutant cells from IDHmutant chondrosarcomas and Idh1mutant murine growth plates. Pharmacologic blockade of glycogen utilization induces changes in tumor cell behavior, downstream energetic pathways, and tumor burden in vitroand 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. |
| Database: |
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