Modelling medulloblastoma pathogenesis and treatment in human cerebellar organoids.
Willott, T. O.; Nicholson, J. G.; Xiao, Y.; Ogunbiyi, O. K.; Mistry, T.; Zabet, N. R.; Merve, A.; Badodi, S.; Marino, S.
Show abstract
Faithful genetically engineered in vivo models of medulloblastoma (MB) are currently available only for some molecular subgroups, in keeping with recent studies showing the unique role of human-specific progenitors in the development of G3 and G4 MB subgroups. We generated human cerebellar organoids (CbO) from expanded potential stem cells (EPSC) and characterised their epigenetic and transcriptomic profile compared to the developing human cerebellum. We show the presence of sub compartment-specific cerebellar lineages linked to MB formation, including populations expressing signature genes of putative G3 and G4 MB cells-of-origin. We show that these lineages can be genetically engineered to model MB tumour onset. Moreover, we demonstrate that CbO sustain proliferation and invasion of G3/4 MB cells in a 3D co-culture model (CbO-MB) while preserving their molecular identity, and that treatment of CbO-MB with anti-tumour compounds recapitulate the efficacy of in vivo drug testing in xenograft models.
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