Human cerebellar organoids to study medulloblastoma pathogenesis and treatment. [scRNA-Seq]

Faithful in vivo models of Group 4 medulloblastoma (G4 MB) are currently unavailable and recent studies showed the unique role of human-specific progenitors in the development of G3 and G4 MB. Here, we obtained cerebellar organoid (CbO) from expanded potential stem cells (EPSC) and developed them in vitro as 3D structures. We performed extensive characterisation of the epigenetic and transcriptomic profile of the mature CbO confirming the presence of sub compartment-specific cerebellar lineages linked to MB formation, including populations expressing signature genes reminiscent of the G3 and G4 MB cell-of-origin never described before. In parallel we have established a protocol to co-culture primary MB cells with our CbO to generate CbO-MB models. We confirmed that CbO sustains MB cells proliferation and invasion while preserving their molecular identity, and that CbO-MB recapitulated the efficacy of in vivo anti-tumour therapy, hence representing a suitable model to gain insight into G3/G4 MB pathogenesis and to set up pre-clinical drug screening.