1. Primary cilia contribute to the aggressiveness of atypical teratoid/rhabdoid tumors
- Author
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Bluemel, Lena, Qin, Nan, Berlandi, Johannes, Paisana, Eunice, Cascao, Rita, Custodia, Carlos, Pauck, David, Picard, Daniel, Langini, Maike, Stuehler, Kai, Meyer, Frauke-Dorothee, Goebbels, Sarah, Malzkorn, Bastian, Liebau, Max C., Barata, Joao T., Jeibmann, Astrid, Kerl, Kornelius, Erkek, Serap, Kool, Marcel, Pfister, Stefan M., Johann, Pascal D., Fruehwald, Michael C., Borkhardt, Arndt, Reifenberger, Guido, Faria, Claudia C., Fischer, Ute, Hasselblatt, Martin, Bartl, Jasmin, Remke, Marc, Bluemel, Lena, Qin, Nan, Berlandi, Johannes, Paisana, Eunice, Cascao, Rita, Custodia, Carlos, Pauck, David, Picard, Daniel, Langini, Maike, Stuehler, Kai, Meyer, Frauke-Dorothee, Goebbels, Sarah, Malzkorn, Bastian, Liebau, Max C., Barata, Joao T., Jeibmann, Astrid, Kerl, Kornelius, Erkek, Serap, Kool, Marcel, Pfister, Stefan M., Johann, Pascal D., Fruehwald, Michael C., Borkhardt, Arndt, Reifenberger, Guido, Faria, Claudia C., Fischer, Ute, Hasselblatt, Martin, Bartl, Jasmin, and Remke, Marc
- Abstract
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.
- Published
- 2022