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 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 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 PDE10A loss have worse outcomes and potentially increased sensitivity to PI3K inhibition.

中文翻译：

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磷酸二酯酶 10A 的单倍体不足激活独立于 PTEN 的 PI3K/AKT 信号转导，以诱导侵袭性胶质瘤表型


胶质母细胞瘤通常是致命的，其特征是频繁的染色体拷贝数改变，带有癌基因和肿瘤抑制因子。在这项研究中，我们分析了外显子组范围的人胶质母细胞瘤拷贝数数据，发现细胞带 6q27 在多个数据集中是一个独立的不良预后标志物。然后，我们将 CRISPR-Cas9 数据、人类空间转录组数据以及人类和小鼠 RNA 测序数据相结合，将 PDE10A 提名为 6q27 区域潜在的单倍体不足肿瘤抑制基因。使用 RCAS/tv-a 系统的小鼠胶质母细胞瘤建模证实，Pde10a 抑制在体内诱导侵袭性胶质瘤表型，在体外诱导对替莫唑胺和放射治疗的耐药性。细胞培养分析显示，Pde10a 表达降低导致 PI3K/AKT 信号转导以 Pten 非依赖性方式增加，这种反应被选择性 PI3K 抑制剂阻断。来自我们小鼠神经胶质瘤体内的单核 RNA 测序与细胞培养验证相结合，进一步表明 Pde10a 抑制与神经到间充质转变有关，该转变表现出细胞粘附增加和细胞迁移减少。我们的结果表明，携带 PDE10A 缺失的胶质母细胞瘤患者的预后较差，并且对 PI3K 抑制的敏感性可能增加。