TMOD-02. GEBTO: GENETICALLY ENGINEERED BRAIN TUMOR ORGANOIDS AS A NOVEL PRECLINICAL MODEL

Jens Bunt, Mieke Roosen, Evie Egelmeers, Zelda Ode, Marcel Kool

Research output: Contribution to journalArticle

Abstract

Background: One of the bottlenecks in basic and translational research on pediatric brain tumors, is the lack of suitable and representative preclinical models to study tumor biology and drug sensitivity. Over the last decades, extensive molecular characterization has uncovered many entities and subgroups with their unique oncodriving events. However, this heterogeneity is currently not reflected in the models available, especially not for in vitro models. Objectives: We aim to generate genetically engineered brain tumor organoids (GEBTO) to represent the molecular variety of embryonal brain tumors and ependymomas. Method: Human brain organoids derived from embryonic stem cells are generated to represent the region of tumor origin. To mimic oncodriving events, DNA plasmids are introduced via electroporation in the organoid cells to knockout tumor suppressor genes or overexpress oncogenes. Results: Cerebellar and cerebral forebrain organoids were generated as the tissue of origin for medulloblastoma and supratentorial ependymoma (ST-EPN), respectively. Based on the detection of GFP protein encoded by DNA plasmids, the organoid cells can be manipulated within a wide developmental window, which corresponds with the presence of the proposed cells of origin. Different oncodrivers and combinations thereof are now being tested to see whether they result in ectopic growth in cerebral or cerebellar organoids. When successful, the GEBTOs are histologically and molecularly characterized using (single cell) transcriptomic and epigenomic analyses to see how well they resemble human tumors. Discussion: Although further development is required, GEBTOs provide a novel avenue to model especially rare pediatric brain tumors, for which tissue and therefore patient-derived models are limited. It also allows for in-depth analyses of the potential cells of origin and the contribution of different mutations to tumor biology.
Original languageEnglish
Pages (from-to)i35-i36
JournalNeuro-Oncology
Volume23
Issue numberSupplement_1
DOIs
Publication statusPublished - 1 Jun 2021

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