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TB-01 HUMAN IPS CELL-DERIVED BRAIN TUMOR MODEL UNCOVERS THE EMBRYONIC STEM CELL SIGNATURE AS A KEY DRIVER IN ATYPICAL TERATOID/RHABDOID TUMOR
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. We established human SMARCB1-deficient pluripotent stem cells (hPSCs), which enabled investigation of...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7213114/ http://dx.doi.org/10.1093/noajnl/vdz039.044 |
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author | Terada, Yukinori Jo, Norihide Arakawa, Yoshiki Mineharu, Yohei Yamada, Yasuhiro Miyamoto, Susumu |
author_facet | Terada, Yukinori Jo, Norihide Arakawa, Yoshiki Mineharu, Yohei Yamada, Yasuhiro Miyamoto, Susumu |
author_sort | Terada, Yukinori |
collection | PubMed |
description | 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. We established human SMARCB1-deficient pluripotent stem cells (hPSCs), which enabled investigation of the pathogenesis of AT/RT. SMARCB1-deficient hPSCs and neural progenitor-like cells (NPLCs) efficiently gave rise to brain tumors when transplanted into mouse brain. Notably, the emergence of typical rhabdoid cells was significantly enhanced in tumors from SMARCB1-deficient hPSCs. An embryonic stem cell (ESC)-like gene expression signature was more prominent in hPSC-derived tumors when compared with NPLCs-derived tumors. Moreover, mice transplanted with SMARCB1-deficient hPSCs showed poor survival than NPLC-transplanted mice. Activation of the ESC-like signature by the forced expression of reprogramming factors conferred a rhabdoid histology in SMARCB1-deficient NPLC-derived tumors, suggesting that acquisition of the ESC-like signature is responsible for the rhabdoid histology. Consistently, we found activation of the ESC-like gene expression signature and an ESC-like DNA methylation landscape in clinical specimens of AT/RT. Mechanistically, c-MYC expression was sufficient to acquire the ESC-like signature and the rhabdoid histology in SMARCB1-deficient NPLC-derived tumors, which resulted in poor survival. Together, SMARCB1-deficient hPSCs offer the first human model for AT/RT, which uncovered the unappreciated role of the activated ESC-like signature in the poor prognosis and unique histology. Finally, we performed a CRISPR/Cas9 knockout screening to inhibit activation of the ESC-like signature in AT/RT. Our effort identified candidate genes as therapeutic targets, including RAD21, which encodes a key component within the cohesin complex. Notably, chemical inhibition of HDAC8, which indirectly targets the function of cohesin, with simultaneous inhibition of EZH2 efficiently suppressed activation of the ESC-like signature and inhibited the growth of AT/RT cells. Collectively, we propose that the ESC-like signature could be a crucial therapeutic target for AT/RTs with rhabdoid histology. |
format | Online Article Text |
id | pubmed-7213114 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-72131142020-07-07 TB-01 HUMAN IPS CELL-DERIVED BRAIN TUMOR MODEL UNCOVERS THE EMBRYONIC STEM CELL SIGNATURE AS A KEY DRIVER IN ATYPICAL TERATOID/RHABDOID TUMOR Terada, Yukinori Jo, Norihide Arakawa, Yoshiki Mineharu, Yohei Yamada, Yasuhiro Miyamoto, Susumu Neurooncol Adv Abstracts 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. We established human SMARCB1-deficient pluripotent stem cells (hPSCs), which enabled investigation of the pathogenesis of AT/RT. SMARCB1-deficient hPSCs and neural progenitor-like cells (NPLCs) efficiently gave rise to brain tumors when transplanted into mouse brain. Notably, the emergence of typical rhabdoid cells was significantly enhanced in tumors from SMARCB1-deficient hPSCs. An embryonic stem cell (ESC)-like gene expression signature was more prominent in hPSC-derived tumors when compared with NPLCs-derived tumors. Moreover, mice transplanted with SMARCB1-deficient hPSCs showed poor survival than NPLC-transplanted mice. Activation of the ESC-like signature by the forced expression of reprogramming factors conferred a rhabdoid histology in SMARCB1-deficient NPLC-derived tumors, suggesting that acquisition of the ESC-like signature is responsible for the rhabdoid histology. Consistently, we found activation of the ESC-like gene expression signature and an ESC-like DNA methylation landscape in clinical specimens of AT/RT. Mechanistically, c-MYC expression was sufficient to acquire the ESC-like signature and the rhabdoid histology in SMARCB1-deficient NPLC-derived tumors, which resulted in poor survival. Together, SMARCB1-deficient hPSCs offer the first human model for AT/RT, which uncovered the unappreciated role of the activated ESC-like signature in the poor prognosis and unique histology. Finally, we performed a CRISPR/Cas9 knockout screening to inhibit activation of the ESC-like signature in AT/RT. Our effort identified candidate genes as therapeutic targets, including RAD21, which encodes a key component within the cohesin complex. Notably, chemical inhibition of HDAC8, which indirectly targets the function of cohesin, with simultaneous inhibition of EZH2 efficiently suppressed activation of the ESC-like signature and inhibited the growth of AT/RT cells. Collectively, we propose that the ESC-like signature could be a crucial therapeutic target for AT/RTs with rhabdoid histology. Oxford University Press 2019-12-16 /pmc/articles/PMC7213114/ http://dx.doi.org/10.1093/noajnl/vdz039.044 Text en © The Author(s) 2019. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology. http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Abstracts Terada, Yukinori Jo, Norihide Arakawa, Yoshiki Mineharu, Yohei Yamada, Yasuhiro Miyamoto, Susumu TB-01 HUMAN IPS CELL-DERIVED BRAIN TUMOR MODEL UNCOVERS THE EMBRYONIC STEM CELL SIGNATURE AS A KEY DRIVER IN ATYPICAL TERATOID/RHABDOID TUMOR |
title | TB-01 HUMAN IPS CELL-DERIVED BRAIN TUMOR MODEL UNCOVERS THE EMBRYONIC STEM CELL SIGNATURE AS A KEY DRIVER IN ATYPICAL TERATOID/RHABDOID TUMOR |
title_full | TB-01 HUMAN IPS CELL-DERIVED BRAIN TUMOR MODEL UNCOVERS THE EMBRYONIC STEM CELL SIGNATURE AS A KEY DRIVER IN ATYPICAL TERATOID/RHABDOID TUMOR |
title_fullStr | TB-01 HUMAN IPS CELL-DERIVED BRAIN TUMOR MODEL UNCOVERS THE EMBRYONIC STEM CELL SIGNATURE AS A KEY DRIVER IN ATYPICAL TERATOID/RHABDOID TUMOR |
title_full_unstemmed | TB-01 HUMAN IPS CELL-DERIVED BRAIN TUMOR MODEL UNCOVERS THE EMBRYONIC STEM CELL SIGNATURE AS A KEY DRIVER IN ATYPICAL TERATOID/RHABDOID TUMOR |
title_short | TB-01 HUMAN IPS CELL-DERIVED BRAIN TUMOR MODEL UNCOVERS THE EMBRYONIC STEM CELL SIGNATURE AS A KEY DRIVER IN ATYPICAL TERATOID/RHABDOID TUMOR |
title_sort | tb-01 human ips cell-derived brain tumor model uncovers the embryonic stem cell signature as a key driver in atypical teratoid/rhabdoid tumor |
topic | Abstracts |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7213114/ http://dx.doi.org/10.1093/noajnl/vdz039.044 |
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