title: mTORC1 maintains the tumorigenicity of SSEA-4(+) high-grade osteosarcoma.
abstract: Inactivation of p53 and/or Rb pathways restrains osteoblasts from cell-cycle exit and terminal differentiation, which underpins osteosarcoma formation coupled with dedifferentiation. Recently, the level of p-S6K was shown to independently predict the prognosis for osteosarcomas, while the reason behind this is not understood. Here we show that in certain high-grade osteosarcomas, immature SSEA-4(+) tumor cells represent a subset of tumor-initiating cells (TICs) whose pool size is maintained by mTORC1 activity. mTORC1 supports not only SSEA-4(+) cell self-renewal through S6K but also the regeneration of SSEA-4(+) TICs by SSEA-4(-) osteosarcoma cell dedifferentiation. Mechanistically, active mTORC1 is required to prevent a likely upregulation of the cell-cycle inhibitor p27 independently of p53 or Rb activation, which otherwise effectively drives the terminal differentiation of SSEA-4(-) osteosarcoma cells at the expense of dedifferentiation. Thus, mTORC1 is shown to critically regulate the retention of tumorigenicity versus differentiation in discrete differentiation phases in SSEA-4(+) TICs and their progeny.
authors: 1] State Key Laboratory for Medical Genomics, Shanghai Institute of Hematology and Collaborative Innovation Center of Hematology, Rui-Jin Hospital affiliated to Shanghai Jiao-Tong University School of Medicine, Shanghai 200025, People's Republic of China [2] Collaborative Innovation Center of Systems Biomedicine, Shanghai 200025, People's Republic of China.
authors: Wu
authors: W
authors: Zhang
authors: State Key Laboratory for Medical Genomics, Shanghai Institute of Hematology and Collaborative Innovation Center of Hematology, Rui-Jin Hospital affiliated to Shanghai Jiao-Tong University School of Medicine, Shanghai 200025, People's Republic of China.
authors: Meng-Lei
authors: ML
authors: Ding
authors: Shanghai Institute of Digestive Surgery, Shanghai 200025, People's Republic of China.
authors: Jia-Nian
authors: JN
authors: Zhang
authors: Division of Orthopedics and Shanghai Institute of Traumatology and Orthopaedics, Shanghai 200025, People's Republic of China.
authors: Jian-Ru
authors: JR
authors: Qiu
authors: Division of Orthopedics and Shanghai Institute of Traumatology and Orthopaedics, Shanghai 200025, People's Republic of China.
authors: Yu-Hui
authors: YH
authors: Shen
authors: Department of Radiology, Rui-Jin Hospital, Shanghai 200025, People's Republic of China.
authors: Xiao-Yi
authors: XY
authors: Ding
authors: Division of Orthopedics and Shanghai Institute of Traumatology and Orthopaedics, Shanghai 200025, People's Republic of China.
authors: Lian-Fu
authors: LF
authors: Deng
authors: Division of Orthopedics and Shanghai Institute of Traumatology and Orthopaedics, Shanghai 200025, People's Republic of China.
authors: Wei-Bin
authors: WB
authors: Zhang
authors: 1] State Key Laboratory for Medical Genomics, Shanghai Institute of Hematology and Collaborative Innovation Center of Hematology, Rui-Jin Hospital affiliated to Shanghai Jiao-Tong University School of Medicine, Shanghai 200025, People's Republic of China [2] Collaborative Innovation Center of Systems Biomedicine, Shanghai 200025, People's Republic of China.
authors: Jiang
authors: J
authors: Zhu
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D002453:Cell Cycle / Q000235:genetics; D054337:Cell Dedifferentiation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D018450:Disease Progression; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005260:Female; D064593:Heterografts; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D060787:Neoplasm Grading; D012516:Osteosarcoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D011379:Prognosis; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism; D055746:Stage-Specific Embryonic Antigens / Q000235:genetics / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D046912:Multiprotein Complexes; D016160:Retinoblastoma Protein; D055746:Stage-Specific Embryonic Antigens; D016159:Tumor Suppressor Protein p53; C066584:stage-specific embryonic antigen-4; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases