EXTH-92. Cellular hierarchies of embryonal tumors with multilayered rosettes are shaped by oncogenic microRNAs and receptor-ligand interactions

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Abstract Embryonal tumors with multilayered rosettes (ETMR) are rare pediatric brain cancers with a median survival of 14 months despite aggressive treatment. The oncogenic driver in ~90% of cases is an amplification and fusion of the chromosome 19 micro-RNA cluster (C19MC), which is yet undruggable. Due to the tumor’s rarity, comprehensive molecular characterization and the identification of therapeutic targets are challenging, and ETMR remains poorly understood. We used single cell RNA sequencing and multiplexed protein profiling to study intratumoral heterogeneity and oncogenic signaling in ETMR (n=11). MiRNA-mRNA interactions were investigated by enhanced crosslinking and immunoprecipitation (eCLIP) followed by next-generation sequencing. ETMR cells were treated with locked nucleic acids (LNAs) and small-molecule inhibitors, and their anti-tumor effects assessed through confluency and death assays. Here, we identified three distinct malignant ETMR cell types resembling differentiation stages during early fetal neocortex development: undifferentiated ETMR cells resembling neural-stem cells (NSC), differentiated cells corresponding to mature neurons, and intermediate cells exerting markers of neuronal lineage commitment. C19MC was overexpressed in mitotically active NSC-like cells. Using eCLIP, we uncovered widespread regulatory roles of individual C19MC members. Markers of neuronal differentiation (NR2F2, SOX4, SOX11) and lineage commitment (C2–H2 ZNF family members) were targets of abundant C19MC members. LNA-mediated blockade of key C19MC members significantly reduced ETMR cell confluency and induced apoptosis. Genome-wide cell-cell communication analysis identified fibroblast growth factor receptors (FGFRs) and NOTCH receptors as key mediators of cellular cooperation. Accordingly, FGFR and NOTCH inhibitors had significant anti-tumor effects in vitro, and erdafitinib-supplemented therapy led to partial response in one therapeutically exhausted ETMR patient. Together, we demonstrated intratumoral heterogeneity in ETMR paralleling fetal neurodevelopment. Targeting C19MC in undifferentiated NSC-like cells significantly impaired cell confluency and survival. Additionally, FGFR emerged as a clinically actionable target, showing promising anti-tumor activity in vitro and in one ETMR patient.

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