Human Pluripotent Stem Cell-Derived Tumor Model Uncovers the Embryonic Stem Cell Signature as a Key Driver in Atypical Teratoid/Rhabdoid Tumor

Cell Rep. 2019 Mar 5;26(10):2608-2621.e6. doi: 10.1016/j.celrep.2019.02.009.


Atypical teratoid/rhabdoid tumor (AT/RT), which harbors SMARCB1 mutation and exhibits a characteristic histology of rhabdoid cells, has a poor prognosis because of the lack of effective treatments. Here, we establish human SMARCB1-deficient pluripotent stem cells (hPSCs). SMARCB1-deficient hPSC-derived neural progenitor-like cells (NPLCs) efficiently give rise to brain tumors when transplanted into the mouse brain. Notably, activation of an embryonic stem cell (ESC)-like signature confers a rhabdoid histology in SMARCB1-deficient NPLC-derived tumors and causes a poor prognosis. Consistently, we find the activation of the ESC-like gene expression signature and an ESC-like DNA methylation landscape in clinical specimens of AT/RT. Finally, we identify candidate genes that maintain the activation of the ESC-like signature and the growth of AT/RT cells. Collectively, SMARCB1-deficient hPSCs offer the human models for AT/RT, which uncover the role of the activated ESC-like signature in the poor prognosis and unique histology of AT/RT.

Keywords: ESC-like signature; SMARCB1; atypical teratoid/rhabdoid tumor; dedifferentiation; embryonic stem cell; induced pluripotent stem cell; pediatric tumor; pluripotency.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Culture Techniques
  • Embryonic Stem Cells / metabolism*
  • Humans
  • Mice
  • Pluripotent Stem Cells / metabolism*
  • Rhabdoid Tumor / drug therapy*
  • Rhabdoid Tumor / genetics*
  • Transfection
  • Xenograft Model Antitumor Assays