Abstract Atypical teratoid/rhabdoid tumors (AT/RT) belong to the most common malignant tumors of the central nervous system during infancy. They split into four major DNA methylation subtypes: AT/RT-TYR, AT/RT-SHH, AT/RT-MYC, and AT/RT-SMARCA4. Each of these subtypes demonstrates distinct molecular fingerprints and clinical characteristics, with AT/RT-TYR most frequently occurring in the fourth ventricle. However, details on the cellular origins and tumor initiation of AT/RT-TYR remain largely unknown and mouse models providing insights into tumor development are completely missing. Therefore, we performed histopathological examination as well as bulk- and single-nucleus RNA sequencing analyses in human AT/RT. Additionally, genetically engineered mouse models with a conditional Cre/loxP-induced Smarcb1 loss were generated. Here, we show that AT/RT-TYR very often appear intermingled with fourth ventricle choroid plexus (CP) tissue and that tumor cells express CP markers on a gene expression and protein level. In addition, we observed a general resemblance of AT/RT-TYR to the CP of the fourth ventricle by analyzing bulk- and single-nucleus RNA sequencing data. Finally, Foxj1-cre::Smarcb1fl/fl mice showing loss of Smarcb1 in early CP progenitors gave rise to large, atypical CP cells with gene expression most similar to human AT/RT-TYR. Further investigation of the CP phenotype via ARL13B immunohistochemistry and transmission electron microscopy demonstrated reduced cilia numbers in Foxj1-cre::Smarcb1fl/fl mice compared to control mice, which was also observed in human AT/RT-TYR compared to healthy CP of the same patient. In conclusion, analyses of human AT/RT-TYR as well as murine CP cells lacking Smarcb1 point towards the CP of the fourth ventricle as a potential cellular origin of AT/RT-TYR.
Altendorf et al. (Tue,) studied this question.