Resolving cellular states underlying medulloblastoma pathogenesis using computational systems biology

The pediatric primary brain tumor medulloblastoma (MB) is a leading cause of cancer-related death in children and characterized by a high degree of inter-patient heterogeneity.

Recent studies performed by the host laboratory and collaborators has contributed to a complete understanding of the cellular origin of all subtypes of MB, which now allows for studies of the early malignant transformation of MB progenitor cells.

Here we present a research proposal in two aims combining state-of-the-art functional genomics and sophisticated computational modeling to model the early tumorigenesis of MB.

In Aim 1, we combine mouse models representative of all MB subgroups with molecular barcodes, single cell transcriptomic and epigenetic profiling and computational modeling to follow the steps of malignant transformation starting from the progenitor cells of MB.

In Aim 2, we make use of a pooled CRISPR/dCas9 activation and inactivation approach to systematically perturb a library of recurrently altered genes in MB. The pooled experiment is implemented in progenitor cells to investigate the effect of altering individual driver genes.

The obtained knowledge will substantiate the lineage and cell state determinants of MB pathogenesis and provide mechanistic insight into why specific genes are recurrently altered in MB molecular subgroups and subtypes.

We believe that the obtained insight can improve MB preclinical models and reveal therapeutic vulnerabilities for improved patient treatment.