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

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

Author information

1
Division of Stem Cell Pathology, Center for Experimental Medicine and Systems Biology, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan; Department of Life Science Frontiers, Center for iPS Cell Research and Application (CiRA), Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan; Department of Neurosurgery, Kyoto University Graduate School of Medicine, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
2
Department of Life Science Frontiers, Center for iPS Cell Research and Application (CiRA), Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
3
Department of Neurosurgery, Kyoto University Graduate School of Medicine, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
4
Division of Stem Cell Pathology, Center for Experimental Medicine and Systems Biology, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan; Department of Life Science Frontiers, Center for iPS Cell Research and Application (CiRA), Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
5
Division of Stem Cell Pathology, Center for Experimental Medicine and Systems Biology, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
6
Department of Life Science Frontiers, Center for iPS Cell Research and Application (CiRA), Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan; AMED-CREST, AMED 1-7-1 Otemachi, Chiyoda-ku, Tokyo 100-0004, Japan; Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
7
Division of Stem Cell Pathology, Center for Experimental Medicine and Systems Biology, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan; Department of Life Science Frontiers, Center for iPS Cell Research and Application (CiRA), Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan; AMED-CREST, AMED 1-7-1 Otemachi, Chiyoda-ku, Tokyo 100-0004, Japan. Electronic address: yasu@ims.u-tokyo.ac.jp.

Abstract

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

PMID:
30840885
DOI:
10.1016/j.celrep.2019.02.009
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