Human pluripotent stem cell-derived brain tumor model uncovered embryonic stem cell signature as a key driver in atypical teratoid/rhabdoid tumor (RNA-Seq)

Atypical teratoid/rhabdoid tumor (AT/RT), which harbors INI1 mutation and exhibits a characteristic histology of rhabdoid cells, has a poor prognosis because of the lack of effective treatments. Here we established human INI1-deficient pluripotent stem cells (hPSCs), which developed AT/RT formation in vivo. We revealed that the activation of ESC-like signature leads to rhabdoid phenotype in tumor by OSKM or c-MYC induction. Finally, we performed CRISPR/Cas9 knockout screening to inhibit activation of ESC-like signature in AT/RT. Our effort identified candidate genes including RAD21 that encodes a key component within the cohesin complex. Notably, chemical inhibition of HDAC8 that indirectly targets the function of cohesin with simultaneous inhibition of EZH2 efficiently suppressed the activation of ESC-like signature and inhibited the growth of AT/RT cells both in vitro and in vivo. Analyzing transcriptional profiles in PSA-NCAM positive NPC INI1-/-; TP53-/- (NPC), GFP-NPC, OSKM-NPC, MYC-NPC and hiPSC INI1-/-; TP53-/--derived tumor cell line treated by DMSO, EZH2 inhibitor, HDAC8 inhibitor or combination of EZH2 and HDAC8 inhibitors.