ZFTA (Zinc Finger Translocation Associated)

Notably, over 80% of genes upregulated in ZFTA-RELAfus tumors were downregulated following MERTK inhibition, indicating a strong dependency on this pathway for tumor maintenance. These findings define a signaling vulnerability in ZFTA-RELA-driven ependymomas and support the clinical development of MERTK-targeted therapies for patients with the high-risk EPN-E1 subtype.

Taken together, our results position itaconate upregulation as a previously unappreciated driver of ZFTA-RELA+ ependymomas. Our work has implications for future drug development to reduce pathogenic ZFTA-RELA expression for this brain tumour, and will advance our understanding of oncometabolites as a new class of therapeutic dependencies in cancers.

Remarkably, normalizing hematopoiesis with a single infusion of antibodies directed against cytokines enriched in the cerebrospinal fluid of mice bearing ZFTA-RELA ependymomas, choroid plexus carcinomas or group 3 medulloblastoma-all aggressive childhood brain tumors-disrupted this process and caused profound tumor regression. These findings demonstrate the existence of a skull bone marrow-tumor immunological interface and suggest that modulating the local supply of myeloid cells could represent a less toxic therapeutic strategy for aggressive childhood brain tumors.

Supratentorial ependymomas with ZFTA-RELA fusions represent a highly aggressive pediatric brain tumor subtype, yet the post-transcriptional mechanisms driving their malignancy remain unclear. This study fills a critical gap by systematically profiling miRNA expression in fusion-positive and fusion-negative supratentorial ependymomas, revealing a distinct fusion-associated miRNA signature. The identification of hsa-miR-138-5p upregulation and hsa-miR-135b-5p/hsa-miR-216a-3p downregulation, converging on key oncogenic nodes such as TERT, YAP1, RELA, and TP53, provides novel mechanistic insight into how fusion-driven miRNA dysregulation enhances epithelial-mesenchymal transition and stemness. The findings suggest that miRNA-fusion interactions play an important role in tumor aggressiveness and highlight hsa-miR-138-5p as a potential biomarker for disease progression. Clinically, the work advances understanding of fusion-driven ependymoma biology and lays the foundation for developing miRNA-based diagnostic and therapeutic strategies targeting molecular mechanisms of tumor progression.

These findings support the concept that conventional histology can capture relevant heterogeneity and may complement molecular studies. The recognition of such features may help refine histopathological assessment and provide practical prognostic insights, particularly in resource-limited settings where molecular testing is not universally available.

Pediatric ependymomas are not uniformly immune-silent. ZFTA-RELA and recurrent tumors exhibit a "primed but suppressed" immune phenotype, where the immune machinery is present but functionally restrained, suggesting greater susceptibility to ICB, whereas PF-A tumors remain immune-excluded and may require microenvironmental modulation to achieve immunotherapy benefit.

DNA methylation profiling successfully classified gynecologic neuroectodermal tumors as known CNS tumor or sarcoma entities. Epigenetic and exomic studies suggest a male genome and increased maternal allelic contribution in CNS-like tumors, suggesting development via conception or chimerism.

The patient underwent gross total resection followed by adjuvant chemoradiotherapy and remains recurrence-free eight years post-treatment. Further investigation of additional cases is warranted to better understand the pathogenesis of this rare tumor.

Posterior fossa ependymomas are now grouped by methylation profile into category A-typical posterior fossa ependymoma and category B which present in older children with smaller lesions with a better prognosis. Spinal ependymoma is relatively unchanged by molecular characterization apart from the new MYCN-altered tumor which has poor prognosis and is often advanced/disseminated at presentation.

In conclusion, ZFTA::NCOA1/2-rearranged epithelioid mesenchymal tumors represent a novel, morphologically distinct entity, genetically and epigenetically overlapping with chondroid lipoma. Expanded cohorts and long-term follow-up are necessary to clarify their precise classification and biologic behavior.

The functionally and spatially defined zones of this model displayed distinct immune presence, with the highest seen in the hypoxic zone. These results provide insights into the molecular heterogeneity and spatial organization of supratentorial ependymomas, which may aid in the development of targeted future treatments.

These results strongly suggest the inclusion of molecular parameters into stratification, and the use of distinct treatment strategies within future ependymoma trials.