TB-01 HUMAN IPS CELL-DERIVED BRAIN TUMOR MODEL UNCOVERS THE EMBRYONIC STEM CELL SIGNATURE AS A KEY DRIVER IN ATYPICAL TERATOID/RHABDOID TUMOR

Abstract

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.