Bluemel, Lena, Qin, Nan, Berlandi, Johannes, Paisana, Eunice, Cascao, Rita ORCID: 0000-0001-5533-9413, Custodia, Carlos, Pauck, David, Picard, Daniel, Langini, Maike ORCID: 0000-0001-8622-3261, 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 (2022). Primary cilia contribute to the aggressiveness of atypical teratoid/rhabdoid tumors. Cell Death Dis., 13 (9). LONDON: SPRINGERNATURE. ISSN 2041-4889

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Bluemel, LenaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Qin, NanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Berlandi, JohannesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Paisana, EuniceUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cascao, RitaUNSPECIFIEDorcid.org/0000-0001-5533-9413UNSPECIFIED
Custodia, CarlosUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pauck, DavidUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Picard, DanielUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Langini, MaikeUNSPECIFIEDorcid.org/0000-0001-8622-3261UNSPECIFIED
Stuehler, KaiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Meyer, Frauke-DorotheeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Goebbels, SarahUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Malzkorn, BastianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Liebau, Max C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Barata, Joao T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jeibmann, AstridUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kerl, KorneliusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Erkek, SerapUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kool, MarcelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pfister, Stefan M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Johann, Pascal D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fruehwald, Michael C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Borkhardt, ArndtUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reifenberger, GuidoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Faria, Claudia C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fischer, UteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hasselblatt, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bartl, JasminUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Remke, MarcUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-692980
DOI: 10.1038/s41419-022-05243-4
Journal or Publication Title: Cell Death Dis.
Volume: 13
Number: 9
Date: 2022
Publisher: SPRINGERNATURE
Place of Publication: LONDON
ISSN: 2041-4889
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
CELLS; STAT1; EXPRESSION; PATHWAY; KIF3AMultiple languages
Cell BiologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/69298

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