SNRPD2-dependency Fuels an Oncogenic Alternative Splicing Repertoire Driving Disease Aggressiveness in Glioma

Gliomas are the most common primary brain tumors, yet the molecular circuits that drive their malignancy remain incompletely defined. Here, using an integrative, multi-dimensional approach, we aimed to pinpoint key molecular drivers having both functional and clinical relevance to disease progression and tumor aggressiveness in gliomas.

Genome-wide CRISPR-Cas9 dependency screen across 70 glioma cell lines was paired with tumor aggressiveness-targeted transcriptomic differential expression and survival analyses to pinpoint critical drivers of disease progression in gliomas. Functional and gene set enrichments as well as protein-protein interaction network analyses were used to identify dominant pathways and key hub genes, followed by independent validation across external transcriptomic and proteomic datasets. Upstream regulator analyses and alternative splicing profiling were performed to nominate regulatory drivers and derive a small nuclear ribonucleoprotein D2 polypeptide (SNRPD2)-associated splicing signature.

Initial screening uncovered 222 essential genes (Chronos<-1) in gliomas, 87 of which were overexpressed in tumors displaying proliferative, epithelial-mesenchymal transition, glycolytic, hypoxic, and inflammatory signatures, and were associated with poor overall survival, consistent with aggressive disease biology. These genes converged on alternative splicing regulation, proteasome function, and cell cycle, with spliceosome core component, SNRPD2 emerging as the top hub gene. High SNRPD2 expression was associated with disease aggressiveness, tumor progression, and adverse clinical outcomes. MYC was identified as a putative transcriptional driver of SNRPD2. High SNRPD2 expression was also linked to differential (oncogenic) alternative splicing of multiple cancer-associated genes, correlating with disease aggressiveness and poor clinical outcomes.

These data establish SNRPD2 and its associated alternatively spliced repertoire as a central adaptive node linked to disease aggressiveness in gliomas, highlighting it as a potential therapeutic target in glioma patients.