Arrested development: the dysfunctional life history of medulloblastoma

Abstract

Medulloblastoma is a heterogeneous embryonal tumor of the cerebellum comprised of four distinct molecular subgroups that differ in their developmental origins, genomic landscapes, clinical presentation, and survival. Recent characterization of the human fetal cerebellum at single-cell resolution has propelled unprecedented insights into the cellular origins of medulloblastoma subgroups, including those underlying previously elusive groups 3 and 4. In this review, the molecular pathogenesis of medulloblastoma is examined through the lens of cerebellar development. In addition, we discuss how enhanced understanding of medulloblastoma origins has the potential to refine disease modeling for the advancement of treatment and outcomes.

Keywords: cerebellum; developmental origins; medulloblastoma; mouse models; organoids; single-cell genomics; stem cell models.

Figure 1.

The molecular subgroups and subtypes of MB. Demographic, clinical, and anatomical features of the four molecular subgroups of MB, supplemented with cellular hierarchies of their respective lineages informed by developmental origins. M⁺ and M0 are depicted by colored and gray portions of the pie chart, respectively. (DN) Desmoplastic/nodular, (MBEN) medulloblastoma with extensive nodularity, (LCA) large cell anaplastic.

Figure 2.

Mouse cerebellar development and inference of WNT-MB and SHH-MB origins from genetically engineered mouse models (GEMMs). (A) Schematic of E11.5 mouse embryo showing derivation of upper RL (red) and lower RL (blue) from rhombomere 1 (r1) and rhombomeres 2–8 (r2–r8), respectively. (B) Schematic of GEMM-informed cellular origin of WNT-MB and SHH-MB. Context-dependent oncogenic alternations hijack normal differentiation trajectories during development, restricting cells in their progenitor states with subsequent induction of MB formation. (Top) Embryonic mouse cerebellum (red). (Bottom) Dorsal brainstem (blue). (Black arrows) Normal differentiation trajectories of GNPs to GNs, and lower RL progenitors to mossy fiber neurons. (Red arrows) Malignant transformation of GNPs and lower RL progenitors upon their respective oncogenic events.

Figure 3.

Novel insights into MB origins through comparative single-cell studies. (A) Developing mouse upper RL at E15.5. Varying expression patterns of Wls, Atoh1, Pax6, Lmx1a, and Eomes molecularly compartmentalize the mouse cerebellar RL into four distinct regions. (iRL) Interior face of the RL, (eRL) exterior face of the RL. (B) Developing human upper RL at 11 postconception weeks (PCW). A vascular bed structurally compartmentalizes the human cerebellar RL into transcriptionally distinct ventricular and subventricular zones (RL^VZ and RL^SVZ). The RL^SVZ contains progenitors to both GluCN/UBC and GN lineages. From single-cell comparative analyses, the cell of origin for group 3/4-MB is suspected to arise from the GluCN/UBC lineage, with group 3-MB developing from early, less differentiated RL^SVZ progenitors and group 4-MB developing from late, more differentiated RL^SVZ progenitors. By 36 PCW, the human upper RL involutes into the posterior vermis, specifically at the nodulus. (RL) Rhombic lip, (EGL) external granule layer, (GNP) granule neuron progenitor, (GN) granule neuron, (GluCN) glutamatergic cerebellar nuclei, (UBC) unipolar brush cell.

Figure 4.

Advanced 2D and 3D systems for modeling MB in human cells. (Top panels) Summary of current 2D and 3D approaches for generating varying types of human pluripotent stem cells and cerebellar organoids as materials for MB modeling. (Bottom panel) Utilization of stem cell-based materials to engineer bona fide human MB models compatible with ex vivo and in vivo propagation. (iPSCs) Induced pluripotent stem cells, (PBMCs) peripheral blood mononuclear cells.