Glioblastoma stem cells reprogram chromatin in vivo to generate selective therapeutic dependencies on DPY30 and phosphodiesterases

Description DPY30 is an in vivo–specific dependency in glioblastoma that regulates phosphodiesterases and angiogenesis in the hypoxic tumor microenvironment. Understanding in vivo cancer dependencies Most studies identifying treatment targets in cancer begin with in vitro screens that do not address the role of the tumor microenvironment (TME). Here, Dixit and colleagues identified DPY30, a regulator of histone H3 lysine 4 trimethylation, as a driver of glioblastoma growth in vivo but not in vitro. By comparing glioblastoma stem cells (GSCs) grown intracranially in mice with those grown in culture, the authors identified that DPY30 regulated angiogenesis and hypoxia pathways in the intracranial TME. Phosphodiesterase (PDE) 4B was identified as a downstream effector of DPY30, and rolipram, a PDE inhibitor, prolonged tumor latency and reduced tumor volumes in mice, with only mild effects on GSCs in vitro. These findings highlight the importance of in vivo assessments of tumor dependencies and suggest PDE inhibition as a potential treatment for glioblastoma. Glioblastomas are universally fatal cancers and contain self-renewing glioblastoma stem cells (GSCs) that initiate tumors. Traditional anticancer drug discovery based on in vitro cultures tends to identify targets with poor therapeutic indices and fails to accurately model the effects of the tumor microenvironment. Here, leveraging in vivo genetic screening, we identified the histone H3 lysine 4 trimethylation (H3K4me3) regulator DPY30 (Dpy-30 histone methyltransferase complex regulatory subunit) as an in vivo–specific glioblastoma dependency. On the basis of the hypothesis that in vivo epigenetic regulation may define critical GSC dependencies, we interrogated active chromatin landscapes of GSCs derived from intracranial patient-derived xenografts (PDXs) and cell culture through H3K4me3 chromatin immunoprecipitation and transcriptome analyses. Intracranial-specific genes marked by H3K4me3 included FOS, NFκB, and phosphodiesterase (PDE) family members. In intracranial PDX tumors, DPY30 regulated angiogenesis and hypoxia pathways in an H3K4me3-dependent manner but was dispensable in vitro in cultured GSCs. PDE4B was a key downstream effector of DPY30, and the PDE4 inhibitor rolipram preferentially targeted DPY30-expressing cells and impaired PDX tumor growth in mice without affecting tumor cells cultured in vitro. Collectively, the MLL/SET1 (mixed lineage leukemia/SET domain-containing 1, histone lysine methyltransferase) complex member DPY30 selectively regulates H3K4me3 modification on genes critical to support angiogenesis and tumor growth in vivo, suggesting the DPY30-PDE4B axis as a specific therapeutic target in glioblastoma.