Human Pluripotent Stem Cell-Derived Tumor Model Uncovers the Embryonic Stem Cell Signature as a Key Driver in Atypical Teratoid/Rhabdoid Tumor
Human Pluripotent Stem Cell-Derived Tumor Model Uncovers the Embryonic Stem Cell Signature as a Key Driver in Atypical Teratoid/Rhabdoid Tumor
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DOI：
10.1016/j.celrep.2019.02.009
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发表时间：
2019-03-05
期刊：
影响因子：
8.8
通讯作者：
Yamada, Yasuhiro
中科院分区：
文献类型：
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作者：
Terada, Yukinori;Jo, Norihide;Yamada, Yasuhiro
不典型畸胎瘤/横纹肌样瘤（AT/RT）携带SMARCB1突变，具有横纹肌样细胞的特征性组织学特征，由于缺乏有效的治疗，预后较差。在这里，我们建立了人类smarcb1缺陷多能干细胞（hPSCs）。smarcb1缺陷的hpsc衍生的神经祖细胞样细胞（nplc）在移植到小鼠大脑时有效地产生脑肿瘤。值得注意的是，胚胎干细胞（ESC）样特征的激活在smarcb1缺陷的nplc源性肿瘤中赋予横纹肌样组织学，并导致预后不良。在AT/RT的临床标本中，我们一致发现了esc样基因表达特征的激活和esc样DNA甲基化景观。最后，我们确定了维持esc样信号激活和AT/RT细胞生长的候选基因。总之，smarcb1缺失的人造血干细胞提供了AT/RT的人类模型，揭示了激活的esc样特征在AT/RT的不良预后和独特组织学中的作用。
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.