Endocrine Abstracts

JOINT898

Brain tumors represent the second most common malignancy in children and adolescents and the leading cause of cancer-related mortality in this population. These tumors are characterized by their resistance to conventional therapies and the severe long-term side effects which involves hormonal imbalances and disruptions in the hypothalamic-pituitary axis. Despite some advances, the molecular causes underlying these tumors remain unclear, and tools for accurate diagnosis/prognosis, and treatment are very limited. Recent data from our group have identified the spliceosome (molecular machinery controlling the RNA splicing-process), as a critical player in the progression/aggressiveness of various endocrine-related cancers, including adult brain tumors. However, the alteration and role of the spliceosome in paediatric brain tumors remains largely unexplored. Herein, we initially analyzed the potential alteration of spliceosome components in seven independent cohorts of paediatric brain tumors (gliomas and medulloblastomas) using bioinformatics tools, identifying a significant overexpression of the spliceosome in tumor vs. non-tumor samples. Notably, some spliceosome alterations were associated with key clinical features, including tumor aggressiveness and survival outcomes. Notably, one spliceosome component (SF1) was found to be overexpressed in diffuse gliomas and medulloblastomas and its expression levels could discriminate between tumor and non-tumor samples. Moreover, higher SF1 levels were associated to higher glioma grades and worse patient outcome (based on survival curves). Interestingly, enrichment analysis revealed a robust correlation between higher SF1 expression levels and key oncogenic signalling-processes, such as MYC, mTOR, and p53 pathways. Functionally, we tested the therapeutic potential of Pladienolide-B, a inhibitor of the spliceosome activity, in different brain tumor cell-models [i.e. glioma (SF188 and KNS42) and medulloblastoma (DAOY) cells, as well as in primary patient-derived cell cultures], which revealed that Pladienolide-B significantly altered critical cancer hallmark features in all cell-models used, including the inhibition of cell proliferation, migration, and stem-like features, and an apoptosis induction. These effects could be mediated by disruptions in key pathways governing cell-cycle progression, cellular-differentiation, and metabolic-pathways signaling. Altogether, our results demonstrate a drastic splicing machinery-associated molecular dysregulation in paediatric brain tumors, which could potentially be considered as a source of novel diagnostic and prognostic biomarkers as well as therapeutic targets. Remarkably, the spliceosome component SF1 is directly associated with characteristics of tumor progression/aggressiveness and patient survival and represents, together with the use of inhibitors of the spliceosome activity, a novel potential therapeutic target/approach to tackle these devastating pathologies.