mTORC1 maintains the tumorigenicity of SSEA-4(+) high-grade osteosarcoma

Wu Zhang; Meng-Lei Ding; Jia-Nian Zhang; Jian-Ru Qiu; Yu-Hui Shen; Xiao-Yi Ding; Lian-Fu Deng; Wei-Bin Zhang; Jiang Zhu

doi:10.1038/srep09604

mTORC1 maintains the tumorigenicity of SSEA-4(+) high-grade osteosarcoma

Sci Rep. 2015 Apr 8:5:9604. doi: 10.1038/srep09604.

Authors

Wu Zhang¹, Meng-Lei Ding², Jia-Nian Zhang³, Jian-Ru Qiu⁴, Yu-Hui Shen⁴, Xiao-Yi Ding⁵, Lian-Fu Deng⁴, Wei-Bin Zhang⁴, Jiang Zhu¹

Affiliations

¹ 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.
² 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.
³ Shanghai Institute of Digestive Surgery, Shanghai 200025, People's Republic of China.
⁴ Division of Orthopedics and Shanghai Institute of Traumatology and Orthopaedics, Shanghai 200025, People's Republic of China.
⁵ Department of Radiology, Rui-Jin Hospital, Shanghai 200025, People's Republic of China.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Bone Neoplasms / drug therapy
Bone Neoplasms / genetics
Bone Neoplasms / metabolism*
Bone Neoplasms / mortality
Bone Neoplasms / pathology*
Cell Cycle / genetics
Cell Dedifferentiation
Cell Transformation, Neoplastic / genetics
Cell Transformation, Neoplastic / metabolism*
Disease Models, Animal
Disease Progression
Epithelial-Mesenchymal Transition / genetics
Female
Heterografts
Humans
Mechanistic Target of Rapamycin Complex 1
Multiprotein Complexes / genetics
Multiprotein Complexes / metabolism*
Neoplasm Grading
Osteosarcoma / drug therapy
Osteosarcoma / genetics
Osteosarcoma / metabolism*
Osteosarcoma / mortality
Osteosarcoma / pathology*
Prognosis
Retinoblastoma Protein / genetics
Retinoblastoma Protein / metabolism
Stage-Specific Embryonic Antigens / genetics
Stage-Specific Embryonic Antigens / metabolism*
TOR Serine-Threonine Kinases / genetics
TOR Serine-Threonine Kinases / metabolism*
Tumor Suppressor Protein p53 / genetics
Tumor Suppressor Protein p53 / metabolism

Substances

Multiprotein Complexes
Retinoblastoma Protein
Stage-Specific Embryonic Antigens
Tumor Suppressor Protein p53
stage-specific embryonic antigen-4
Mechanistic Target of Rapamycin Complex 1
TOR Serine-Threonine Kinases