Mutant IDH regulates glycogen metabolism from early cartilage development to malignant chondrosarcoma formation
Sinthu Pathmanapan,
Raymond Poon,
Tomasa Barrientos De Renshaw,
Puviindran Nadesan,
Makoto Nakagawa,
Gireesh A. Seesankar,
Adrian Kwan Ho Loe,
Hongyuan H. Zhang,
Joan J. Guinovart,
Jordi Duran,
Christopher B. Newgard,
Jay S. Wunder,
Benjamin A. Alman
Affiliations
Sinthu Pathmanapan
Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, ON, Canada; Institute of Medical Science, University of Toronto, Toronto, ON, Canada
Raymond Poon
Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, ON, Canada
Tomasa Barrientos De Renshaw
Department of Orthopaedic Surgery, Duke University, Durham, NC, USA
Puviindran Nadesan
Department of Orthopaedic Surgery, Duke University, Durham, NC, USA
Makoto Nakagawa
Department of Orthopaedic Surgery, Duke University, Durham, NC, USA
Gireesh A. Seesankar
Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, ON, Canada
Adrian Kwan Ho Loe
Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, ON, Canada
Hongyuan H. Zhang
Department of Orthopaedic Surgery, Duke University, Durham, NC, USA
Joan J. Guinovart
Institute for Research in Biomedicine (IRB Barcelona) Barcelona, Barcelona, Spain
Jordi Duran
Institute for Research in Biomedicine (IRB Barcelona) Barcelona, Barcelona, Spain
Christopher B. Newgard
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
Jay S. Wunder
Lunenfeld-Tanenbaum Research Institute and the University Musculoskeletal Oncology Unit, Mount Sinai Hospital, Toronto, ON, Canada
Benjamin A. Alman
Department of Orthopaedic Surgery, Duke University, Durham, NC, USA; Corresponding author
Summary: 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.
