Phd in GENETICS AND MOLECULAR BIOLOGY

Thesis title: From mechanisms to nanoparticle targeting: toward a lncRNA-based therapy in Medulloblastoma

RNA therapies involve the use of RNA-based molecules for the treatment or prevention of different diseases and are being rapidly developed to address pathological conditions that are often untreatable with traditional drug classes, such as cancer. A potential role for long non-coding-based RNA therapies has been highlighted to precisely modulate gene expression networks involved in diseases, paving the way for innovative and tailored treatments. Group 3 (G3) is one of the most frequent and aggressive subtypes of the pediatric cerebellar tumor Medulloblastoma (MB), associated with a poor prognosis. Most G3 MB cases are driven by the MYC oncogene, whose direct targeting has long been challenging. Additionally, molecular networks underlying G3 MB remain incompletely defined, further hindering the development of gene- or mechanism-directed therapies. In this context, the widespread involvement of long noncoding RNAs (lncRNAs) in cancer, their tumor-selective expression, and their association with MYC biology emphasize the importance to explore their roles, to uncover novel insights and targets. Here, we provide the functional and mechanistic characterization of lncMB3, which we previously identified as MYC-dependent anti-apoptotic lncRNA in G3 MB. Using -omic and functional assays, we demonstrate that lncMB3 regulates genes involved in the TGF-β pathway, a critical player in G3 MB pathogenesis. This axis operates via lncMB3 physical interaction with the mRNA encoding the epigenetic factor HMGN5, and converges on apoptosis through OTX2, another key driver in G3 MB. The significance of this network is further highlighted by the synergistic effects between lncMB3 targeting and cisplatin treatment in vitro. Lastly, we propose ferritin-based nanocarriers as an efficient tool for delivering antisense oligonucleotides against lncMB3 in G3 MB cells. Our findings establish lncMB3 as a crucial hub in G3 MB, linking MYC amplification to the inhibition of cell death, through a circuit comprising both well-described and underexplored MB factors. These results lay the groundwork for translating non-coding RNA research into therapeutic strategies for G3 MB.