Modeling pediatric medulloblastoma

Abstract

Mouse models of medulloblastoma have proven to be instrumental in understanding disease mechanisms, particularly the role of epigenetic and molecular drivers, and establishing appropriate preclinical pipelines. To date, our research community has developed murine models for all four groups of medulloblastoma, each of which will be critical for the identification and development of new therapeutic approaches. Approaches to modeling medulloblastoma range from genetic engineering with CRISPR/Cas9 or in utero electroporation, to orthotopic and patient-derived orthotopic xenograft systems. Each approach or model presents unique advantages that have ultimately contributed to an appreciation of medulloblastoma heterogeneity and the clinical obstacles that exist for this patient population.

Keywords: Group 3; Group 4; MYC; MYCN; Sonic hedgehog; WNT; medulloblastoma; mouse models; patient-derived xenografts.

Figure 1

Summary of technical methods and approaches to medulloblastoma modeling.

Figure 2

For each subgroup of medulloblastoma, the proportions of driver events as determined by Next‐Generation Sequencing (NSG) are displayed; Copy Number Variants (CNV) and mutation analysis. Modeled Drivers: of all driver events identified by NGS for this subgroup, the proportion represented by established in vivo models. Other: Driver events identified by NGS which have not been modeled in vivo. Unexplained Cases: cases of this MB group for which no events have been identified through NGS approaches. Recently, defined subdivisions of groups into subgroups are also displayed 14, with those in bold having corresponding in vivo models.