MODL-41. LOSS OF DISTAL CHROMOSOME 6Q AND ASSOCIATED PDE10A INDUCES AN AGGRESSIVE GLIOMA PHENOTYPE BY FACILITATING PRONEURAL TO MESENCHYMAL TRANSITION

Somatic copy number alterations (SCNAs) are common in glioblastoma, with some SCNAs having prognostic implications. Identifying and characterizing SCNA-related genes acting as oncogenes or tumor suppressors may potentially provide new therapeutic avenues for gliomas. In this study, we sought to uncover novel SCNA-related genes by employing an unbiased log rank analysis screen of genomic regions associated with glioblastoma survival. We identified 6q27 loss as an independent poorly-prognostic SCNA across three separate glioblastoma cohorts. An in vitro CRISPR screen using human neural stem cells identified five genes in the 6q27 region that caused increased cellular proliferation. One of these genes, phosphodiesterase 10A (PDE10A), had a gene dosage effect on expression and decreased expression in human and mouse glioma tumor tissue compared to normal brain, which are both common tumor suppressor phenotypes. Knockdown of Pde10a in mouse neural stem cells in vitro validated the human cell CRISPR screen phenotype. Suppression of Pde10a in RCAS/Tva mouse glioma in vivo caused decreased survival with increased tumor grade, mitotic activity, necrosis, Vegfa expression, and AKT/pS6 signaling. Single cell RNA-sequencing of mouse gliomas revealed that Pde10a suppression results in a shift from proneural to mesenchymal-like state. In human glioma tissue, PDE10A loss is also associated with an increased mesenchymal signature. Top activated pathways in Pde10a suppressed gliomas involved cell-cell interaction, including upregulation of cell adhesion molecules and downregulation of focal adhesion complex disassembly genes. Functional analysis in vitro confirmed that Pde10a suppression results in increased extracellular matrix adhesion and decreased migration. Relevant to standard glioblastoma treatment, PDE10A loss was associated with decreased MGMT promoter methylation, decreased DNA methyltransferase gene expression, and it potentiated radiation resistance in vitro. In summary, we leveraged several multiomic and experimental platforms to reveal PDE10A as a tumor suppressor in glioblastoma, predominantly by inducing a proneural to mesenchymal transition phenotype.