ATRT-07. TARGETING PRIMARY CILIOGENESIS IN ATYPICAL TERATOID/RHABDOID TUMORS

Abstract Atypical teratoid/rhabdoid tumors (AT/RT) are among the most common malignant brain tumors in infants. Comprehensive genomic studies revealed three distinct molecular subgroups (AT/RT-TYR, -MYC and -SHH). As primary cilia (PC) have already been shown to play a pivotal role in other tumor en...

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Published in:Neuro-oncology (Charlottesville, Va.) Va.), 2019-04, Vol.21 (Supplement_2), p.ii64-ii64
Main Authors: Blümel, Lena, Kerl, Kornelius, Qin, Nan, Berlandi, Johannes, Thiel, Katharina, Tegeder, Isabel, Jeibmann, Astrid, Paisana, Eunice, Custódia, Carlos, Picard, Daniel, Langini, Maike, Stühler, Kai, Meyer, Frauke-Dorothee, Malzkorn, Bastian, Liebau, Max C, Johann, Pascal D, Erkek, Serap, Kool, Marcel, Pfister, Stefan M, Frühwald, Michael C, Faria, Cláudia C, Borkhardt, Arndt, Reifenberger, Guido, Hasselblatt, Martin, Remke, Marc
Format: Article
Language:English
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Atypical Teratoid Rhabdoid Tumor (ATRT)
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Summary:Abstract Atypical teratoid/rhabdoid tumors (AT/RT) are among the most common malignant brain tumors in infants. Comprehensive genomic studies revealed three distinct molecular subgroups (AT/RT-TYR, -MYC and -SHH). As primary cilia (PC) have already been shown to play a pivotal role in other tumor entities, we aimed to characterize the distribution of PC across AT/RT subgroups and to target primary ciliogenesis in these tumors with dismal prognosis. We performed immunofluorescence to detect PC in AT/RT primary tumor sections and cell lines. The functional role of PC was investigated in vitro by knockdown of KIF3A. The relevance of primary ciliogenesis in AT/RT biology was further elucidated in vivo using a fly model of SMARCB1 deficiency and an orthotopic mouse model. We detected PC in all AT/RT primary tumor sections and cell lines investigated in this study. Notably, we observed a significant subgroup-specific difference in the proportion of PC-positive cells. Specifically, AT/RT-TYR demonstrated the highest percentage of ciliated cells. Knockdown of KIF3A significantly reduced cell proliferation and stem cell properties. Additionally, apoptosis was significantly increased via upregulation of JAK1/STAT1 signaling. In a fly model of SMARCB1 deficiency, concomitant knockdown of several cilia-associated genes resulted in a substantial shift of the lethal phenotype with >20% of flies reaching adulthood. Finally, we demonstrated a significantly prolonged survival in an orthotopic xenograft model upon knockdown of KIF3A. In conclusion, our results implicate PC as a key feature of AT/RT biology and suggest primary ciliogenesis as a potential therapeutic target, especially in AT/RT-TYR.
ISSN:1522-8517
1523-5866
DOI:10.1093/neuonc/noz036.006