biostudies-literatureNuechterlein NNational Institute of Neurological Disorders and StrokeNational Cancer InstituteNCI NIH HHSNINDS NIH HHSNational Institutes of HealthNational Science Foundation273-288https://www.ebi.ac.uk/biostudies/studies/S-EPMC11065166biostudies-literatureUnknown38(5-6)Glioblastoma is universally fatal and characterized by frequent chromosomal copy number alterations harboring oncogenes and tumor suppressors. In this study, we analyzed exome-wide human glioblastoma copy number data and found that cytoband 6q27 is an independent poor prognostic marker in multiple data sets. We then combined CRISPR-Cas9 data, human spatial transcriptomic data, and human and mouse RNA sequencing data to nominate <i>PDE10A</i> as a potential haploinsufficient tumor suppressor in the 6q27 region. Mouse glioblastoma modeling using the RCAS/tv-a system confirmed that Pde10a suppression induced an aggressive glioma phenotype in vivo and resistance to temozolomide and radiation therapy in vitro. Cell culture analysis showed that decreased Pde10a expression led to increased PI3K/AKT signaling in a Pten-independent manner, a response blocked by selective PI3K inhibitors. Single-nucleus RNA sequencing from our mouse gliomas in vivo, in combination with cell culture validation, further showed that Pde10a suppression was associated with a proneural-to-mesenchymal transition that exhibited increased cell adhesion and decreased cell migration. Our results indicate that glioblastoma patients harboring <i>PDE10A</i> loss have worse outcomes and potentially increased sensitivity to PI3K inhibition.Genes & developmentHaploinsufficiency of phosphodiesterase 10A activates PI3K/AKT signaling independent of PTEN to induce an aggressive glioma phenotype.PMC11065166R35 CA253119DGE-1762114R01 NS119650K08 CA245037Intramural Research ProgramChittaboina PCasad MBrown DTang KGilbert MRAldape KStoica SHolland ECStella NPattwell SBanasavadi-Siddegowda YKShelbourn AJackson SSulman EPatel APArowa SPratt DShapiro LArora SCimino PJWirsching HGMerino-Galan LPaddison PNuechterlein NSzulzewsky FAlvinez NJung MAbdullaev ZfalseHaploinsufficiency of phosphodiesterase 10A activates PI3K/AKT signaling independent of PTEN to induce an aggressive glioma phenotype.Glioblastoma is universally fatal and characterized by frequent chromosomal copy number alterations harboring oncogenes and tumor suppressors. In this study, we analyzed exome-wide human glioblastoma copy number data and found that cytoband 6q27 is an independent poor prognostic marker in multiple data sets. We then combined CRISPR-Cas9 data, human spatial transcriptomic data, and human and mouse RNA sequencing data to nominate <i>PDE10A</i> as a potential haploinsufficient tumor suppressor in the 6q27 region. Mouse glioblastoma modeling using the RCAS/tv-a system confirmed that Pde10a suppression induced an aggressive glioma phenotype in vivo and resistance to temozolomide and radiation therapy in vitro. Cell culture analysis showed that decreased Pde10a expression led to increased PI3K/AKT signaling in a Pten-independent manner, a response blocked by selective PI3K inhibitors. Single-nucleus RNA sequencing from our mouse gliomas in vivo, in combination with cell culture validation, further showed that Pde10a suppression was associated with a proneural-to-mesenchymal transition that exhibited increased cell adhesion and decreased cell migration. Our results indicate that glioblastoma patients harboring <i>PDE10A</i> loss have worse outcomes and potentially increased sensitivity to PI3K inhibition.2024-01-01T00:00:00Z2024 Apr2026-05-04T06:48:48.739Z2025-04-06T13:45:20.677ZS-EPMC110651663858903410.1101/gad.351350.123