Medulloblastoma is the most common solid primary brain tumor in children. Remarkable advancements in the understanding of the genetic and epigenetic basis of these tumors have informed their recent molecular classification. However, the genotype/phenotype correlation of the subgroups remains largely uncharacterized. In particular, the metabolic phenotype is of great interest because of its druggability, which could lead to the development of novel and more tailored therapies for a subset of medulloblastoma. p73 plays a critical role in a range of cellular metabolic processes. We show overexpression of p73 in a proportion of non-WNT medulloblastoma. In these tumors, p73 sustains cell growth and proliferation via regulation of glutamine metabolism. We validated our results in a xenograft model in which we observed an increase in survival time in mice on a glutamine restriction diet. Notably, glutamine starvation has a synergistic effect with cisplatin, a component of the current medulloblastoma chemotherapy. These findings raise the possibility that glutamine depletion can be used as an adjuvant treatment for p73-expressing medulloblastoma.

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Sonic Hedgehog (SHH) medulloblastomas are brain tumours that arise in the posterior fossa. Cancerpropagating cells (CPCs) provide a reservoir of cells capable of tumour regeneration and relapse post-treatment. Understanding and targeting the mechanisms by which CPCs are maintained and expanded in SHH medulloblastoma could present novel therapeutic opportunities. We identified the aryl hydrocarbon receptor (AHR) pathway as a potent tumour suppressor in a SHH medulloblastoma mouse model. Ahr-deficient tumours and CPCs grown in vitro, showed elevated activation of the tGfβ mediator, SMAD3. Pharmacological inhibition of the TGFβ/SMAD3 signalling axis was sufficient to inhibit the proliferation and promote the differentiation of Ahr-deficient CPCs. Human SHH medulloblastomas with high expression of the AHR repressor (AHRR) exhibited a significantly worse prognosis compared to AHRR low tumours in two independent patient cohorts. Together, these findings suggest that reduced AHR pathway activity promotes SHH medulloblastoma progression, consistent with a tumour suppressive role for AHR. We propose that TGFβ/SMAD3 inhibition may represent an actionable therapeutic approach for a subset of aggressive SHH medulloblastomas characterised by reduced AHR pathway activity. Medulloblastoma represents one of the most common forms of paediatric, malignant brain tumours accounting for around 20% of all paediatric tumours of the CNS 1. Typical treatment consists of a combination of chemotherapy, surgical resection and neuraxis irradiation, with a cure rate of approximately 70-75% in children ≥3 years of age 2. However, survivors of medulloblastoma are left with a host of long-term adverse sequelae, including cognitive deficits, problems with neuroendocrine function and fertility 3,4. These drawbacks to traditional treatment options necessitate more effective patient stratification strategies based on biomarkers that predict outcome and identify specific molecular medulloblastoma subtypes for personalized, targeted therapies. Efforts to dissect the molecular underpinnings of medulloblastoma have identified four main subgroups-WNT, Sonic hedgehog (SHH), Group 3 and Group 4-with distinct transcriptional, DNA methylation and mutational profiles, and different clinical characteristics and outcomes 5-7. These subgroups are associated with different cells of origin 8. SHH tumours originate from cerebellar granule cell progenitors (GCPs), and display excessive activation of the SHH signalling pathway 9. The prognosis of SHH subgroup medulloblastomas is mixed, with

The identification of key tumorigenic events in Sonic Hedgehog subgroup medulloblastomas (MBSHH) will be essential for the development of individualized therapies and improved outcomes. However, beyond confirmation of characteristic SHH-pathway mutations, recent genome-wide sequencing studies have not revealed commonly-mutated genes with widespread relevance as potential therapeutic targets. We therefore examined any role for epigenetic DNA methylation events in MBSHH using a cross-species approach to candidate identification, prioritization and validation. MBSHH–associated DNA methylation events were first identified in 216 subgrouped human medulloblastomas (50 MBSHH, 28 WNT, 44 Group 3, 94 Group 4) and their conservation then assessed in tumors arising from four independent murine models of Shh medulloblastoma, alongside any role in tumorigenesis using functional assessments in mouse and human models. This strategy identified widespread regional CpG hypo-methylation of VAV1, leading to its elevated expression, as a conserved aberrant epigenetic event which characterizes the majority of MBSHH tumors in both species, and is associated with a poor outcome in MBSHH patients. Moreover, direct modulation of VAV1 in mouse and human models revealed a critical role in tumor maintenance, and its abrogation markedly reduced medulloblastoma growth. Further, Vav1 activity regulated granule neuron precursor (GNP) germinal zone exit and migration initiation in an ex vivo model of early post-natal cerebellar development. These findings establish VAV1 as a critical epigenetically-regulated oncogene with a key role in MBSHH maintenance, and highlight its potential as a validated therapeutic target and prognostic biomarker for the improved therapy of medulloblastoma.