MODL-39 - Elucidating the transcriptomic landscape of metastatic pediatric Medulloblastoma

Medulloblastoma (MB) is a highly aggressive and the most common brain tumor in childhood. MB presents a high intertumoral heterogeneity, with at least four molecular subgroups (SHH, WNT, Group 3, and Group 4) identified. MB can metastasize to the leptomeningeal space, known as Leptomeningeal Disease (LMD) and its presence is a universal predictor of poor outcome among MB patients. Metastatic MB is predominantly found in the MB Group 3 type. Although LMD represents a main clinical challenge, its molecular mechanisms remain poorly characterized. Recent research has shown that primary and MB metastasis diverge dramatically. Our work has focused on establishing therapy naïve Group 3 Patient-Derived Xenografts that faithfully replicate the nature of primary and metastatic Medulloblastoma with the aim to perform comparative genomic and transcriptomic analyses between these models to identify genetic drivers/pathways that sustain metastatic MB or leptomeningeal disease. Our results show various signaling pathways enriched across LMD models, such as protein secretion and oxidative phosphorylation. We also have identified differentially expressed genes, where sets of genes have shown to be present in more than one PDX model, such as members of the Solute Carriers family (SLC44A3 and SLC17A9) and FCGBP. Retrieval of short variants from RNAseq data has not revealed thus far mutations enriched in LMD, suggesting these changes could be attributed to epigenetic disruption rather than genetic changes. In conclusion, our results support the notion that primary and LMD are transcriptionally different, with various enriched pathways and sets of DEG among LMD Group 3 PDX models. These findings are in progress for functional validation. Work is currently being done to profile the epigenome of LMD by correlating transcriptomic data with active chromatin markers such as H3K27ac and H3K4me1. Through these approaches, we aim to elucidate the genetic dependencies of metastatic Medulloblastoma that will help for targeted therapies.