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Therapeutic interventions induce cell stress to trigger apoptosis in tumor cells. Specific cellular stressors, including those initiated by radio-chemotherapy, activate distinct pro-death proteins through a multitude of mechanisms. Apoptosis consists of highly regulated pathways involving post-translational modifications and cleavage of proteins leading to sequential inactivation of the main cellular processes e.g. cell cycle progression. Recently, we demonstrated that apoptotic bodies/ApoEVs in GBM transfer spliceosomal machinery components to neighboring cells, which are subsequently internalized and confer survival advantage through changes in mRNA splicing. Following the validation of the role of RBM11, a spliceosomal component in the said intercellular communication, we extended our findings in the characterization of spatially distinct clonally derived sphere lines from tumor edge and core-located tissues from GBM patients. We analyzed the expression of spliceosomal genes in edge and core-derived clones and found spatially distinct splicing capabilities and that the genes that were affected by alternative splicing events in edge and core cells have different splicing of genes that are involved in ubiquitination and regulate cell cycle progression. Downstream analyses revealed that the most promising target is MDM2. Importantly, this gene regulates cell cycle via ubiquitination. Further, western blot revealed differential expression of both RBM11 and MDM2 in egde and core-derived clones.Collectively, the data so far provides motivation for the possibility of finding cellular vulnerabilities in the splicing machinery and thus actionable targets for intervention that accounts for the bearings of spatial heterogeneity.

CSIG-28. ROLE OF ALTERNATIVE SPLICING IN CONFERRING SPATIAL HETEROGENEITY SIGNATURES IN GBM