Background
Supratentorial RELA fusion (ST-RELA) ependymomas (EPNs) are resistant tumors without an approved chemotherapeutic treatment. Unfortunately, the molecular mechanisms that leads to chemoresistance traits of ST-RELA remains elusive. The aim of this study was to assess RELA fusion-dependent signaling modules, specifically the role of the Hedgehog (Hh) pathway as a novel targetable vulnerability in ST-RELA.
Methods
Gene expression was analyzed in EPN from patient cohorts, by microarray, RNA-seq, qRT-PCR, and scRNA-seq. Inhibitors against Smoothened (SMO) (Sonidegib) and Aurora-kinase A (AURKA) (Alisertib) were evaluated. Protein expression, primary cilia formation, and drug effects were assessed by immunoblot, immunofluorescence and immunohistochemistry.
Results
Hh components were selectively overexpressed in EPNs induced by the RELA fusion. Single-cell analysis showed that the Hh signature was primarily confined to undifferentiated, stem-like cell subpopulations. Sonidegib exhibited potent growth-inhibitory effects on ST-RELA cells, suggesting a key role for active Hh signaling; importantly, the effect of Sonidegib was reversed by primary cilia loss. We thus tested the effect of AURKA inhibition by Alisertib, to induce cilia stabilization/reassembly. Strikingly, Alisertib rescued ciliogenesis and synergized with Sonidegib in killing ST-RELA cells. Using a xenograft model, we show that cilia loss is a mechanism for acquiring resistance to the inhibitory effect of Sonidegib. However, Alisertib fails to rescue cilia and highlights the need for other strategies to promote cilia reassembly, for treating ST-RELA tumors.
Conclusion
Our study reveals a crucial role for the Hh pathway in ST-RELA tumor growth, and suggests that rescue of primary cilia represents a vulnerability of the ST-RELA EPNs.
HUWE1cooperates with RAS activation to control leukemia cell proliferation and human hematopoietic stem cells differentiation fate. Cancer Gene Therapy, (10-11), 830-833.
The Group 3 Medulloblastoma ( Grp3-MB ) is an aggressive molecular subtype with a high incidence of metastasis and deaths. In this study, were used an RNA sequencing data ( RNA-Seq ) from a Brazinian cohort of MBs to identify hub genes associated with the metastatic risk. Data validation were performed by using multiple large datasets from MBs (GSE85217, GSE37418, EGAS00001001953). DESeq2 package in R software was used to identify the differentially expressed genes ( DEGs ) in our RNA-Seq data. The DEGs data were accessed to construct the modules/graphs of coexpression and to identify hub genes through Cytoscape platform. The co-regulated genes were enriched by the Kyoto Encyclopedia of Genes and Genomes ( KEGG ) pathway and the Protein-protein interaction ( PPI ) network was visualized by Cytoscape. The Kaplan-Meier plotter and ROC curves were used to validate the diagnostic and prognostic values of speci c biomarkers identi ed through this model. We identi ed that Inositol 1,4,5triphosphate receptor type 1 ( ITPR1 ) as a downregulated hub gene, with a high diagnostic accuracy to Grp3-MBs and associated with tumor metastasis. In addition, we identi ed genes signi cantly correlated with ITPR1 that were associated with metastasis in Grp3-MB ( ATP1A2 , MTTL7A and RGL1) , and worst overall survival in MBs ( ANTXR1 and RGL1 ). Our ndings suggest that the ITPR1 hub gene is potentially involved in the metastatic process for Grp3-MB. Our data also provide evidence of targets that may serve as prognostic predictors and/or regulators for the metastatic process that maybe explored for further research of individualized therapy to Grp3-MBs.
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