Analysis of Paediatric Medulloblastoma cellular heterogeneity using Single-cell transcriptomic profiling for improved therapeutic strategies

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Brain tumours are the leading cause of cancer-related death inchildren. Medulloblastoma (MB) is the most common malignant paediatric braintumour with a third of all patients already metastatic at diagnosis. Group3 MB subtype(G3) predominates in infants and young children, has the lowest survival rate andhighest incidence of metastasis (47%). Almost 100% of children with recurrent G3post-treatment have metastases. Currently, standard-of-care treatment is multi-modaland highly aggressive, leaving young survivors with severe long-term cognitive andgrowth impairments, and secondary malignancies. The advancement of G3 researchto develop therapies are limited by two major factors. The paucity of appropriate cellmodels and the ability to deconvolute the brain's cellular complexity at the molecularlevel. This proposal leverages next-generation 3D in vitro models that accuratelyrecapitulate the brain's cellular architecture, G3 metastatic initiation/progression andrelapse after therapy. For G3 deconvolution, single-cell transcriptomics will be utilizedto discover genes and regulatory networks driving cellular trajectories of G3 clinicalsubtypes. Additionally, high-dimensional statistical modelling based on geneexpression profiles will allow us to develop biomarkers to precisely predict G3evolution and treatment sensitivity at time of diagnosis and highlight translationaltargets for effective personalised therapeutic strategies and improved quality of life.