Atypical teratoid rhabdoid tumors (ATRTs) are challenging pediatric brain cancers that are predominantly associated with inactivation of the gene SMARCB1, a conserved subunit of the chromatin remodeling BAF complex, which has known contributions to developmental processes. To identify potential interactions between SMARCB1 loss and the process of neural development, we introduced an inducible SMARCB1 loss-of-function system into human induced pluripotent stem cells (iPSCs) that were subjected to either directed neuronal differentiation or differentiation into cerebral organoids. Using this system, we identified substantial differences in the downstream effects of SMARCB1 loss depending on differentiation state and identified an interaction between SMARCB1 loss and neural differentiation pressure that causes a resistance to terminal differentiation and a defect in maintenance of a normal cell state. Our results provide insight into how SMARCB1 loss might interact with neural development in the process of ATRT tumorigenesis.
Bibliographical noteFunding Information:
We thank Dr. Bruce Conklin for providing CRISPR interference cell lines and constructs, and Dr. Diana Hargreaves for provision of BAF complex antibodies. In addition, we thank Rachel Reed and Dr. Ciro Zanca, Dr. Jorge Benitez, Dr. Jianhui Ma, Dr. Amy Haseley Thorne, Dr. Nathan Jameson, and Dr. Tiffany Taylor for their technical contributions to this project, and Dr. Gene Yeo, Dr. Robert Wechsler-Reya, Dr. Rafael Bejar, Dr. Alysson Muotri, and Dr. Lorraine Pillus for their continued advice and mentorship. This work was supported by Padres Pedal the Cause/RADY grant (PTC2017), the National Institute of General Medical Sciences (T32GM008666; to A.D.P.), the National Institute of Neurological Diseases and Stroke (R01-NS080939; to F.B.F.), and a Japan Society for the Promotion of Science (JSPS) Overseas Research Fellowship (S.M.). This publication includes data generated at the UC San Diego IGM Genomics Center using an Illumina NovaSeq 6000 that was purchased with funding from a National Institutes of Health SIG grant (S10 OD026929).
© 2020 Parisian et al.
- BAF complex
- Neural development
- Tumor modeling