Abstract Background Ependymomas are brain tumors, arising in the central nervous system in both children and adults. Supratentorial ependymomas (ST-EPN) are predominantly driven by YAP1- and ZFTA-fusion proteins, which are linked to distinct molecular subtypes and clinical outcomes. Methods To study tumorigenesis of these ST-EPN types in a human background in vitro, we generated and molecularly characterized YAP1- and ZFTA-fusion driven models using cerebral brain organoids derived from human embryonic stem cells. Results Single cell transcriptome analyses of cerebral brain organoids developing over time demonstrated a high abundance of radial glia-like progenitor cells, the proposed cellular origin of EPN, in eleven days old organoids. In older organoids, the abundance of these cells went down as they matured into more differentiated cell types. Organoids electroporated at day 11 with either YAP1- or ZFTA-fusion expressing plasmids developed ectopic masses mimicking histological and molecular features of human ST-EPN tumors. Both YAP1- and ZFTA-fusion positive organoids were tumorigenic when engrafted into the mouse brain. Single-cell transcriptomic analyses of the organoids demonstrated that cells overexpressing the YAP1-fusion show a skewed differentiation towards radial glial lineages, while overexpression of the ZFTA-fusion results in a more neuronal differentiation trajectory, consistent with observations in patient-derived tumors. Moreover, we identified interactions between tumor cells and non-neoplastic developing brain cells, which may promote tumorigenesis and could potentially be targeted therapeutically. Conclusion Our findings demonstrate that cerebral brain organoids can be used to study the tumorigenesis and biology of supratentorial ependymomas in vitro in a human context of a non-malignant environment.
Roosen et al. (Thu,) studied this question.