A recombinant lentiviral PDGF-driven mouse model of proneural glioblastoma

• Published in: Neuro-oncology (Charlottesville, Va.) Vol. 20; no. 3; pp. 332 - 342
• Main Authors: Rahme, Gilbert J, Luikart, Bryan W, Cheng, Chao, Israel, Mark A
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 19-02-2018
• Subjects: Animals; Basic and Translational Investigations; Brain Neoplasms - genetics; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; Cell Proliferation; Cell Transformation, Neoplastic; Cyclin-Dependent Kinase Inhibitor p16 - genetics; Cyclin-Dependent Kinase Inhibitor p16 - metabolism; Disease Models, Animal; Female; Glioblastoma - genetics; Glioblastoma - metabolism; Glioblastoma - pathology; Humans; Lentivirus - genetics; Lymphokines - genetics; Lymphokines - metabolism; Male; Mice; Mice, Inbred C57BL; Mice, SCID; Mice, Transgenic; Platelet-Derived Growth Factor - genetics; Platelet-Derived Growth Factor - metabolism; Signal Transduction; Tumor Cells, Cultured
• ISSN: 1522-8517; 1523-5866
• DOI: 10.1093/neuonc/nox129

Mouse models of glioblastoma (GBM), the most aggressive primary brain tumor, are critical for understanding GBM pathology and can contribute to the preclinical evaluation of therapeutic agents. Platelet-derived growth factor (PDGF) signaling has been implicated in the development and pathogenesis of GBM, specifically the proneural subtype. Although multiple mouse models of PDGF-driven glioma have been described, they require transgenic mice engineered to activate PDGF signaling and/or impair tumor suppressor genes and typically represent lower-grade glioma.
We designed recombinant lentiviruses expressing both PDGFB and a short hairpin RNA targeting Cdkn2a to induce gliomagenesis following stereotactic injection into the dentate gyrus of adult immunocompetent mice. We engineered these viruses to coexpress CreERT2 with PDGFB, allowing for deletion of floxed genes specifically in transduced cells, and designed another version of this recombinant lentivirus in which enhanced green fluorescent protein was coexpressed with PDGFB and CreERT2 to visualize transduced cells.
The dentate gyrus of injected mice showed hypercellularity one week post-injection and subsequently developed bona fide tumors with the pathologic hallmarks of GBM leading to a median survival of 77 days post-injection. Transcriptomic analysis of these tumors revealed a proneural gene expression signature.
Informed by the genetic alterations observed in human GBM, we engineered a novel mouse model of proneural GBM. While reflecting many of the advantages of transgenic mice, this model allows for the facile in vivo testing of gene function in tumor cells and makes possible the rapid production of large numbers of immunocompetent tumor-bearing mice for preclinical testing of therapeutics.