Blümel, L., Qin, N., Berlandi, J., Paisana, E., Cascão, R., Custódia, C., Pauck, D., Picard, D., Langini, M., Stühler, K., Meyer, F.D., Göbbels, S., Malzkorn, B., Liebau, M.C., Barata, J.T., Jeibmann, A., Kerl, K., Erkek, S., Kool, M., Pfister, S.M., Johann, P.D., Frühwald, M.C., Borkhardt, A., Reifenberger, G., Faria, C.C., Fischer, U., Hasselblatt, M., Bartl, J., Remke, M. (2022). Primary cilia contribute to the aggressiveness of atypical teratoid/rhabdoid tumors.  Cell Death Dis. 13(9): 806.

FBrf0254570

Research paper

Atypical teratoid/rhabdoid tumor (AT/RT) is a highly malignant brain tumor in infants that is characterized by loss of nuclear expression of SMARCB1 or SMARCA4 proteins. Recent studies show that AT/RTs comprise three molecular subgroups, namely AT/RT-TYR, AT/RT-MYC and AT/RT-SHH. The subgroups show distinct expression patterns of genes involved in ciliogenesis, however, little is known about the functional roles of primary cilia in the biology of AT/RT. Here, we show that primary cilia are present across all AT/RT subgroups with specific enrichment in AT/RT-TYR patient samples. Furthermore, we demonstrate that primary ciliogenesis contributes to AT/RT biology in vitro and in vivo. Specifically, we observed a significant decrease in proliferation and clonogenicity following disruption of primary ciliogenesis in AT/RT cell line models. Additionally, apoptosis was significantly increased via the induction of STAT1 and DR5 signaling, as detected by proteogenomic profiling. In a Drosophila model of SMARCB1 deficiency, concomitant knockdown of several cilia-associated genes resulted in a substantial shift of the lethal phenotype with more than 20% of flies reaching adulthood. We also found significantly extended survival in an orthotopic xenograft mouse model of AT/RT upon disruption of primary ciliogenesis. Taken together, our findings indicate that primary ciliogenesis or its downstream signaling contributes to the aggressiveness of AT/RT and, therefore, may constitute a novel therapeutic target.

PMC9489777 (PMC) (EuropePMC)