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

• Published in: Cell reports (Cambridge) Vol. 26; no. 10; pp. 2608 - 2621.e6
• Main Authors: Terada, Yukinori, Jo, Norihide, Arakawa, Yoshiki, Sakakura, Megumi, Yamada, Yosuke, Ukai, Tomoyo, Kabata, Mio, Mitsunaga, Kanae, Mineharu, Yohei, Ohta, Sho, Nakagawa, Masato, Miyamoto, Susumu, Yamamoto, Takuya, Yamada, Yasuhiro
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 05.03.2019; Elsevier
• Subjects: atypical teratoid/rhabdoid tumor; dedifferentiation; embryonic stem cell; ESC-like signature; induced pluripotent stem cell; pediatric tumor; pluripotency; SMARCB1; SMARCB1; embryonic stem cell; induced pluripotent stem cell; pediatric tumor; dedifferentiation; pluripotency; atypical teratoid/rhabdoid tumor; ESC-like signature
• ISSN: 2211-1247; 2211-1247
• 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. [Display omitted] •SMARCB1-deficient human iPSCs give rise to AT/RT-like tumors•ESC-like signature induces rhabdoid histology and causes a poor prognosis•AT/RT exhibits ESC-like transcriptional signature and DNA methylation landscape•ESC-like signature could be a therapeutic target for AT/RT Terada et al. present SMARCB1-deficient human pluripotent stem cell-derived atypical teratoid/rhabdoid tumor (AT/RT) models and show that ESC-like signature is a critical driver of malignant phenotypes of AT/RT. Genetic ablation targeting the maintenance of pluripotency inhibits AT/RT cell growth, suggesting that the ESC-like signature could be a promising therapeutic target for AT/RT.