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

摘要

Atypical teratoid/rhabdoid tumor (AT/RT), which harborsSMARCB1 mutation and exhibits a characteristichistology of rhabdoid cells, has a poor prognosisbecause of the lack of effective treatments. Here,we establish human SMARCB1-deficient pluripotentstem cells (hPSCs). SMARCB1-deficient hPSCderivedneural progenitor-like cells (NPLCs) efficientlygive rise to brain tumors when transplanted into themouse brain. Notably, activation of an embryonicstem cell (ESC)-like signature confers a rhabdoid histologyin SMARCB1-deficient NPLC-derived tumorsand causes a poor prognosis. Consistently, we findthe activation of the ESC-like gene expression signatureand an ESC-like DNA methylation landscape inclinical specimens of AT/RT. Finally, we identifycandidate genes that maintain the activation of theESC-like signature and the growth of AT/RT cells.Collectively, SMARCB1-deficient hPSCs offer thehuman models for AT/RT, which uncover the role ofthe activated ESC-like signature in the poor prognosisand unique histology of AT/RT.