Ependymoma group-specific blood-brain barrier differences uncovered by a multi-omics approach.
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A significant obstacle in treating brain tumors is the limited drug penetration across the blood-brain barrier (BBB), characterized by an interplay of endothelial tight junctions and efflux pumps. Brain tumors can alter BBB characteristics; however, there is limited understanding in ependymoma (EPN), the third most common pediatric brain tumor. To this end, we characterized EPN tumor (n = 364) and healthy brain tissues (n = 225) at RNA level and identified a distinct EPN group-specific BBB transcriptional pattern. Analyses of public datasets from Aubin and Gojo as well as a validation single-cell dataset (n = 8) could further specify a novel BBB signature expressed in an endothelial subpopulation. Clinically relevant drugs (n = 3) that were effective against EPN in vitro were further evaluated for BBB penetration in our subtype-specific patient-derived xenograft (PDX) models. Idasanutlin showed overall low brain-to-plasma ratios, while the P-glycoprotein (PGP) substrates temsirolimus and etoposide accumulated slightly more in zinc finger translocation associated (ZFTA)-fusion positive EPN than in PFA tumors and adjacent brain. These differences align with modestly lower PGP levels in ZFTA PDX, although expression does not necessarily reflect transporter activity and was not consistently observed in patient tumors. Despite these differences, all tested drugs remained below their effective in vitro levels. In summary, multi-omics analyses of BBB characteristics improve the understanding of drug penetrance and may potentially guide treatment choices in the context of molecular EPN groups within upcoming clinical trials.