Distal chromosome 6q harbors a haploinsufficient tumor suppressor gene that regulates PI3K signaling in glioblastoma

Glioblastoma is a universally fatal disease characterized by remarkable molecular heterogeneity. Prognostic biomarkers in glioblastoma have implications for patient management and drug development but are currently limited. In this study, we analyzed exome-wide human glioblastoma somatic copy number alteration data and discovered cytoband 6q27 as an independent poor prognostic marker across multiple glioblastoma datasets. We then combined CRISPR-Cas9 data, human spatial transcriptomic data, and human and mouse RNA sequencing data to nominate PDE10A 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. Cell culture analysis showed that decreased Pde10a expression led to increased Pi3k/Akt signaling, a response blocked by selective Pi3k inhibitors. Single nucleus RNA sequencing from our mouse gliomas in vivo, in combination with cell culture validation showed that Pde10a suppression was associated with a proneural to a mesenchymal transition that exhibited increased cell adhesion and decreased cell migration. PDE10A loss was associated with unmethylated MGMT promoter status in human glioblastoma and resistance to temozolomide and radiation therapy in vitro. Our results indicate that patients with glioblastoma harboring PDE10A loss have worse outcomes, increased resistance to standard-of-care therapy, and potentially increased sensitivity to PI3K inhibition. We targeted Pde10a with shRNAs in mouse neural stem cells deficient in Cdkn2a