EPCO-45. CELLULAR HIERARCHIES OF ETMR ARE SHAPED BY ONCOGENIC MICRORNAS AND RECEPTOR-LIGAND INTERACTIONS

• Published in: Neuro-oncology (Charlottesville, Va.) Va.), 2023-11, Vol.25 (Supplement_5), p.v134-v134
• Main Authors: Gabler, Lisa, Beck, Alexander, Cruzeiro, Gustavo, Lambo, Sander, Englinger, Bernhard, Shaw, McKenzie L, Hack, Olivia, Chi, Susan, Alexandrescu, Sanda, Gojo, Johannes, Kool, Marcel, Hovestadt, Volker, Filbin, Mariella
• Format: Article
• Language: English
• Subjects: (Epigenetics) and Computational Omics
• ISSN: 1522-8517; 1523-5866
• DOI: 10.1093/neuonc/noad179.0507

Abstract Embryonal tumor with multilayered rosettes (ETMR) is a highly aggressive brain tumor that predominantly occurs in children under the age of four years. Most children succumb within 10 months of diagnosis, typically due to invasive tumor growth and therapy-refractory behavior. 95% of ETMR harbor activating genetic alterations of the chromosome 19 microRNA cluster (C19MC). Despite the identification of this presumed oncogenic driving event, its biological consequences remain understudied and targeted therapy options are lacking. Here, we set out to further explore the intracellular heterogeneity of ETMR and shed light onto its oncogenic mechanisms with the goal to identify novel therapeutic targets for this dismal disease. We have compiled and analyzed a cohort of 11 ETMR tumors using single-cell RNA sequencing and multiplexed spatial imaging. We reveal a common, spatially distinct cellular hierarchy, closely resembling physiological brain development. This hierarchy spans a highly proliferative neural stem cell-like population that gives rise to more differentiated neuron-like cells. C19MC, predominantly expressed in the malignant stem-like population, controls a transcriptional network governing stemness and lineage commitment, as resolved by genome-wide analysis of microRNA-mRNA interactions. Targeting specific C19MC members by antisense oligonucleotides results in reduced cell proliferation, suggesting potent new avenues for future therapeutic approaches. Seeking more immediate therapeutic targets, we performed comprehensive cell-cell interaction analyses and reveal that FGF-FGFR and Delta-Notch interactions are important to maintain oncogenic signaling across malignant cell populations. These interactions were successfully targeted using small molecule inhibitors in preclinical models and in one ETMR patient. Taken together, we identify different malignant ETMR cell populations that follow a common developmental hierarchy, explore the regulatory reach of C19MC activation, and identify an oncogenic receptor-ligand interaction network. Targeting this interaction network opens a powerful new rationale for more effective ETMR therapies.