Generation of diffuse intrinsic pontine glioma mouse models by brainstem-targeted in utero electroporation. Issue 3 (22nd October 2019) - Patel, Smruti K
Abstract: Background: Diffuse intrinsic pontine gliomas (DIPGs) are highly lethal childhood brain tumors. Their unique genetic makeup, pathological heterogeneity, and brainstem location all present challenges to treatment. Developing mouse models that accurately reflect each of these distinct features will be critical to advance our understanding of DIPG development, progression, and therapeutic resistance. The aims of this study were to generate new mouse models of DIPG and characterize the role of specific oncogenic combinations in DIPG pathogenesis. Methods: We used in utero electroporation (IUE) to transfect neural stem cells in the developing brainstem with PiggyBac DNA transposon plasmids. Combinations of platelet-derived growth factor B (PDGFB), Pdgfra D842V, or Pdgfra WT, combined with dominant negative Trp53 (DNp53) and H3.3 K27M expression, induced fully penetrant brainstem gliomas. Results: IUE enabled the targeted transfection of brainstem neural stem cells. PDGFB + DNp53 + H3.3 K27M induced the rapid development of grade IV gliomas. Pdgfra D842V + DNp53 + H3.3 K27M produced slower forming grade III gliomas. Pdgfra WT + DNp53 + H3.3 K27M produced high- and low-grade gliomas with extended latencies. PDGFB, Pdgfra D842V, and Pdgfra WT DIPG models display unique histopathological and molecular features found in human DIPGs. H3.3 K27M induced both overlapping and unique gene expression changes in PDGFB and Pdgfra D842V tumors. Paracrine effects of PDGFB promote disruption of pericyte-endothelial interactions and angiogenesis in PDGFB DIPG mouse models. Conclusion: Brainstem-targeted IUE provides a rapid and flexible system to generate diverse DIPG mouse models. Using IUE to investigate mutation and pathohistological heterogeneity of DIPG will provide a valuable tool for future genetic and preclinical studies.