Primary cilia contribute to the aggressiveness of atypical teratoid/rhabdoid tumors

ABSTRACT: Atypical teratoid/rhabdoid tumor (AT/RT) is the most common malignant brain tumor in infants and is characterized by loss of nuclear SMARCB1 protein expression. Recent studies show that AT/RTs comprise three molecular subgroups with epigenetic differences, including distinct expression patterns of genes involved in ciliogenesis, but little is known on the functional role 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. 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. Finally, we demonstrated significantly extended survival in an orthotopic xenograft mouse model of AT/RT upon disruption of primary ciliogenesis, confirming a survival benefit across different species with SMARCB1 deficiency. Altogether, our findings indicate that targeting primary ciliogenesis or its downstream signaling may constitute a novel therapeutic approach for AT/RT.

INSTRUMENT(S): LTQ Orbitrap Elite

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Brain

DISEASE(S): Brain Cancer

SUBMITTER: Gereon Poschmann  

LAB HEAD: Kai Stühler

PROVIDER: PXD027211 | Pride | 2022-10-14

REPOSITORIES: Pride