Abstract
Group 3 (G3) is one of the most common and aggressive subtypes of the paediatric cerebellar tumour Medulloblastoma (MB), primarily driven by the MYC oncogene. The challenging targeting of MYC, coupled with gaps in understanding G3 MB molecular bases, has hindered the development of targeted therapies. The unconventional oncogenic roles of long noncoding RNAs (lncRNAs) offer opportunities to address this complexity, to provide insights and to identify novel targets. Using -omics approaches and molecular/cellular assays, we elucidate the mode-of-action of lncMB3, a MYC-dependent, anti-apoptotic lncRNA in G3 MB. LncMB3 regulates the TGF-β pathway, critically altered in G3 medulloblastomagenesis, via direct binding and translational inhibition of the mRNA for the epigenetic factor HMGN5. This regulatory axis affects apoptosis through photoreceptor lineage genes, including the G3 driver OTX2. The synergistic effects between lncMB3 targeting and cisplatin treatment underscore the relevance of this network. Additionally, we propose novel ferritin-based nanocarriers for the efficient delivery of antisense oligonucleotides against lncMB3. LncMB3 crucially links MYC amplification and apoptosis inhibition through a circuit involving RNA-based mechanisms, G3 MB key determinants and underexplored factors. This integrated framework deepens the understanding of G3 MB landscape and supports the potential for translating lncRNA research into future applications.