The distorted, noncoding logic of a paediatric brain cancer

Background and objectives. Group 3 is among the most aggressive molecular subgroups of medulloblastoma (MB), the most common malignant brain tumour of childhood, and is frequently associated with metastatic dissemination, poor clinical outcome, and activation of MYC-dependent oncogenic programmes. Although MYC is a central driver of tumour aggressiveness, its broad and pleiotropic roles in proliferation, differentiation, cell-state maintenance, and metabolism, together with its intrinsically disordered and largely undruggable structure, make direct therapeutic targeting particularly challenging. This has prompted the search for more disease-restricted vulnerabilities within regulatory layers associated with, and functionally required by, MYC-driven tumour states. In this context, long noncoding RNAs (lncRNAs) represent attractive candidates, as they can display tissue- and disease-specific expression and may contribute to the organisation of subgroup-specific regulatory programmes. Despite extensive genomic and transcriptomic characterisation of Group 3 MB, the functional contribution of lncRNAs to its aggressive phenotype remains insufficiently explored (Laneve et al., 2020). Methodology and results. Building on our previous identification of MYC-regulated lncRNAs in Group 3 MB cells (Rea et al., 2021), we prioritised lncMB1 and lncMB3 as candidates for functional, mechanistic, and translational investigation. LncMB3 emerged as a pro-survival factor, as its depletion induces apoptosis in Group 3 MB cells. Mechanistically, lncMB3 modulates the TGF-β pathway through RNA-RNA interactions involving HMGN5, thereby reshaping a photoreceptor-like transcriptional programme linked to apoptotic control. This mode of action has recently been defined, together with translational efforts aimed at combining lncRNA targeting with chemotherapy and nanocage-based RNA drug delivery (Grandioso et al., 2025). In parallel, steric-blocking antisense oligonucleotides are being developed to disrupt pathological lncRNA-dependent complexes in Group 3 MB cells. LncMB1 is transcribed antisense to RHOT1, a key regulator of 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 analyses aim to define the molecular basis through which lncMB1 preserves MT homeostasis. Conclusions. Our findings identify lncMB3 and lncMB1 as disease-relevant lncRNAs controlling complementary hallmarks of Group 3 MB aggressiveness: apoptotic resistance and MT dynamics. These results support the concept that the noncoding transcriptome contributes functionally to paediatric tumour biology and may expose RNA-based therapeutic vulnerabilities in the most aggressive MB subgroups. References. 1. Laneve P, Caffarelli E. The Non-coding Side of Medulloblastoma. Frontiers in Cell and Developmental Biology. 2020;8:275. doi:10.3389/fcell.2020.00275. 2. Rea J, Carissimo A, Trisciuoglio D, Illi B, Picard D, Remke M, Laneve P, Caffarelli E. Identification and Functional Characterization of Novel MYC-Regulated Long Noncoding RNAs in Group 3 Medulloblastoma. Cancers. 2021;13(15):3853. doi:10.3390/cancers13153853. 3. Grandioso A, Tollis P, Pellegrini FR, Falvo E, Palma A, Migliaccio F, Belvedere A, Rea J, Tisci G, Carissimo A, Bozzoni I, Trisciuoglio D, Ballarino M, Ceci P, Laneve P. The MYC-dependent lncRNA MB3 inhibits apoptosis in Group 3 Medulloblastoma by regulating the TGF-β pathway via HMGN5. Cell Death & Disease. 2025;16:800. doi:10.1038/s41419-025-08097-8.