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), PdgfraD842V, or PdgfraWT, combined with dominant negative Trp53 (DNp53) and H3.3K27M expression, induced fully penetrant brainstem gliomas. RESULTS:IUE enabled the targeted transfection of brainstem neural stem cells. PDGFB + DNp53 + H3.3K27M induced the rapid development of grade IV gliomas. PdgfraD842V + DNp53 + H3.3K27M produced slower forming grade III gliomas. PdgfraWT + DNp53 + H3.3K27M produced high- and low-grade gliomas with extended latencies. PDGFB, PdgfraD842V, and PdgfraWT DIPG models display unique histopathological and molecular features found in human DIPGs. H3.3K27M induced both overlapping and unique gene expression changes in PDGFB and PdgfraD842V 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.
journal_name
Neuro Oncoljournal_title
Neuro-oncologyauthors
Patel SK,Hartley RM,Wei X,Furnish R,Escobar-Riquelme F,Bear H,Choi K,Fuller C,Phoenix TNdoi
10.1093/neuonc/noz197subject
Has Abstractpub_date
2020-03-05 00:00:00pages
381-392issue
3eissn
1522-8517issn
1523-5866pii
5602255journal_volume
22pub_type
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