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

Abstract

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