mTORC1 Maintains the Tumorigenicity of SSEA-4+ High-Grade Osteosarcoma

نویسندگان

  • 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
چکیده

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.

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عنوان ژورنال:

دوره 5  شماره 

صفحات  -

تاریخ انتشار 2015