The dark side of Medulloblastoma

Medulloblastoma (MB) is the most common pediatric brain tumor. Despite improved survival, treatments still impose long-term sequelae, underscoring the need for molecularly informed therapies. Although integrated omics has defined four MB molecular subgroups with distinct signatures and drivers, the contribution of long non-coding RNAs (lncRNAs) to subgroup-specific programs remains insufficiently explored. We focused on Group 3 (G3) MB, the most aggressive subgroup, marked by high metastatic burden, poor outcome and frequent MYC amplification. Building on our previous identification of MYC-dependent lncRNAs in G3 MB (Rea et al., 2021), we prioritized lncMB1 and lncMB3 for functional investigation. LncMB3 emerged as a pro-survival factor, as its depletion induces apoptosis. Mechanistically, lncMB3 modulates the TGF-β pathway through RNA-RNA interactions involving HMGN5, reshaping a photoreceptor-like transcriptional program linked to apoptotic control in G3 MB cells. This mode of action has recently been defined (Grandioso et al., 2025), together with translational efforts including combination of lncRNA targeting with chemotherapy and nanocage-based RNA drug delivery. In parallel, competitive ASOs are being developed to disrupt pathological complexes in G3 MB cells. LncMB1 is transcribed antisense to RHOT1, a key regulator of microtubule-dependent mitochondrial (MT) trafficking. Its depletion reduces RHOT1 mRNA and protein abundance, downregulates gene sets associated with MT metabolism, and causes fragmentation and redistribution of the MT network. Ongoing RNA pulldown RNA-seq, mass spectrometry, and untargeted metabolomics aim to define the basis through which lncMB1 preserves MT homeostasis. Overall, our findings identify lncMB3 and lncMB1 as core MYC-dependent lncRNAs controlling complementary hallmarks of G3 MB aggressiveness, apoptotic signaling and MT dynamics, and support their candidacy as RNA-based therapeutic vulnerabilities in the deadliest MB subgroup.