Development of an orthotopic medulloblastoma zebrafish model for rapid drug testing

van Bree, Niek; Oppelt, Ann-Sophie; Lindström, Susanne; Zhou, Leilei; Boutin, Lola; Coyle, Beth; Swartling, Fredrik J; Johnsen, John Inge; Bräutigam, Lars; Wilhelm, Margareta

Abstract

Background

Medulloblastoma (MB) is one of the most common malignant brain tumors in children. Current preclinical in vivo model systems for MB have increased our understanding of molecular mechanisms regulating MB development. However, they may not be suitable for large-scale studies. The aim of this study was to investigate if a zebrafish-based xenograft model can recapitulate MB growth and enable rapid drug testing.

Methods

Nine different MB cell lines or patient-derived cells were transplanted into blastula-stage zebrafish embryos. Tumor development and migration were then monitored using live imaging. RNA sequencing was performed to investigate transcriptome changes after conditioning cells in neural stem cell-like medium. Furthermore, drug treatments were tested in a 96-well format.

Results

We demonstrate here that transplantation of MB cells into the blastula stage of zebrafish embryos leads to orthotopic tumor growth that can be observed within 24 hours after transplantation. Importantly, the homing of transplanted cells to the hindbrain region and the aggressiveness of tumor growth are enhanced by pre-culturing cells in a neural stem cell-like medium. The change in culture conditions rewires the transcriptome towards a more migratory and neuronal phenotype, including the expression of guidance molecules SEMA3A and EFNB1, both of which correlate with lower overall survival in MB patients. Furthermore, we highlight that the orthotopic zebrafish MB model has the potential to be used for rapid drug testing.

Conclusion

Blastula-stage zebrafish MB xenografts present an alternative to current MB mouse xenograft models, enabling quick evaluation of tumor cell growth, neurotropism, and drug efficacy.

Citation

van Bree, N., Oppelt, A.-S., Lindström, S., Zhou, L., Boutin, L., Coyle, B., Swartling, F. J., Johnsen, J. I., Bräutigam, L., & Wilhelm, M. (2024). Development of an orthotopic medulloblastoma zebrafish model for rapid drug testing. Neuro-Oncology, https://doi.org/10.1093/neuonc/noae210

• Journal Article Type: Article
• Acceptance Date: Oct 7, 2024
• Online Publication Date: Oct 9, 2024
• Publication Date: Oct 9, 2024
• Deposit Date: Oct 24, 2024
• Publicly Available Date: Oct 28, 2024
• Journal: Neuro-Oncology
• Print ISSN: 1522-8517
• Electronic ISSN: 1523-5866
• Publisher: Oxford University Press
• Peer Reviewed: Peer Reviewed
• DOI: https://doi.org/10.1093/neuonc/noae210
• Keywords: medulloblastoma, neurotropism, patient-derived xenografts, rapid drug testing, zebrafish
• Public URL: https://nottingham-repository.worktribe.com/output/40705660
• Publisher URL: https://academic.oup.com/neuro-oncology/advance-article/doi/10.1093/neuonc/noae210/7816290