Deconstructing Sonic Hedgehog Medulloblastoma: Molecular Subtypes, Drivers, and Beyond

SHH-MBs are characterized by pathogenic activation of SHH signaling. Continued exploration of the somatic and germline molecular landscapes have revealed alterations in a variety of functional processes, including chromatin modulation and post-transcriptional gene regulation. Intertumoral heterogeneity amongst SHH-MB subgroup tumors has been described in terms of molecular subtypes (α, β, γ, and δ) with distinctive patient demographics, genetic lesions, and clinical outcomes. Developmental origins of SHH-MB have been pinpointed to the GN lineage with age-associated distinctions in cellular and differentiation hierarchies. Over 40% of pediatric SHH-MBs exhibit damaging germline mutations, while such events are much rarer among adults. Quiescent, therapy-resistant cells, such as SOX2+ and OLIG2+ progenitor cells, may serve as reservoirs for tumor regrowth in relapsed SHH-MB. Divergent clonal selection may drive recurrence through selective pressures imposed by therapy. Medulloblastoma (MB) is a highly malignant cerebellar tumor predominantly diagnosed during childhood. Driven by pathogenic activation of sonic hedgehog (SHH) signaling, SHH subgroup MB (SHH-MB) accounts for nearly one-third of diagnoses. Extensive molecular analyses have identified biologically and clinically relevant intertumoral heterogeneity among SHH-MB tumors, prompting the recognition of novel subtypes. Beyond germline and somatic mutations promoting constitutive SHH signaling, driver alterations affect a multitude of pathways and molecular processes, including TP53 signaling, chromatin modulation, and post-transcriptional gene regulation. Here, we review recent advances in the underpinnings of SHH-MB in the context of molecular subtypes, clarify novel somatic and germline drivers, highlight cellular origins and developmental hierarchies, and describe the composition of the tumor microenvironment and its putative role in tumorigenesis. Medulloblastoma (MB) is a highly malignant cerebellar tumor predominantly diagnosed during childhood. Driven by pathogenic activation of sonic hedgehog (SHH) signaling, SHH subgroup MB (SHH-MB) accounts for nearly one-third of diagnoses. Extensive molecular analyses have identified biologically and clinically relevant intertumoral heterogeneity among SHH-MB tumors, prompting the recognition of novel subtypes. Beyond germline and somatic mutations promoting constitutive SHH signaling, driver alterations affect a multitude of pathways and molecular processes, including TP53 signaling, chromatin modulation, and post-transcriptional gene regulation. Here, we review recent advances in the underpinnings of SHH-MB in the context of molecular subtypes, clarify novel somatic and germline drivers, highlight cellular origins and developmental hierarchies, and describe the composition of the tumor microenvironment and its putative role in tumorigenesis. comprises the brain, spinal cord, optic nerves, and retina. The CNS receives information and feedback from the sensory organs and from nerves throughout the body, processes the information, and controls the response to those stimuli. a mutational phenomenon characterized by massive, clustered genomic rearrangements. Chromosomes that undergo chromothripsis first fragment into many pieces and are then stitched back together in a random order by DNA repair processes, most likely nonhomologous end joining. a transient zone of granule cell precursors that is formed from cells that migrate tangentially from the uRL to cover the pial surface of the developing cerebellum. animals that harbor genetic alterations artificially introduced by humans and have been broadly used to study genetic disorders. a highly proliferative population that gives rise to GN. GNPs remain mitotically active in the EGL during the first postnatal week in mice and then start to migrate and differentiate into GNs once they reach the IGL. glutamatergic excitatory neurons located in the IGL of the cerebellar cortex. Granule cells extend their axons into the molecular layer where they synapse with Purkinje cells. modify histones by means of catalyzing the transfer of an acetyl group from acetyl-CoA to the ε-amino group of a histone lysine residue. Epigenetic activity of HATs facilitates transcriptional access to DNA by either neutralizing the positive histone charge or serving as a binding site for chromatin remodeling complexes. final position in the cerebellum where cells from the EGL migrate and differentiate into mature GNs. modified RNA nucleotides in which the ribose moiety is modified with an extra bridge connecting the 2′ oxygen and 4′ carbon. LNAs have been used for the detection of low-abundance nucleic acids and chromosomal DNA due to their increased sensitivity compared with DNA and RNA oligos/probes. mutations that result in reduced or total ablation of normal protein function. an embryonal cerebellar tumor that is among the most common malignant pediatric brain tumors and a leading cause of cancer-related death among children. MB is divided into biologically and clinically distinct molecular subgroups – WNT, SHH, Group 3, and Group 4. SHH signaling is a signal transduction cascade that regulates key events during developmental processes such as growth and the patterning of multicellular embryos. The regulatory action of SHH signaling is precisely linked to the secretion, uptake, and translocation of SHH ligand. represent a major component of the tumor microenvironment in SHH-MBs. TAMs have been proposed to play a role in tumor growth, metastatic dissemination, and treatment failure. TAMs release cytokines and induce antiapoptotic programs in transformed GNPs. an adaptive response triggered by endoplasmic reticulum (ER) stress that reduces the unfolded protein load to maintain cell viability and function. a primary germinal zone of the developing cerebellum. The uRL gives rise to numerous glutamatergic neuronal populations during development, including GNPs, cerebellar nuclei, and unipolar brush cells.