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Imagining ways to prevent or treat glioblastoma (GBM) has been hindered by a lack of understanding of its pathogenesis. Although overexpression of platelet derived growth factor with two A-chains (PDGF-AA) may be an early event, critical details of the core biology of GBM are lacking. For example, existing PDGF-driven models replicate its microscopic appearance, but not its genomic architecture. Here we report a model that overcomes this barrier to authenticity. Using a method developed to establish neural stem cell cultures, we investigated the effects of PDGF-AA on subventricular zone (SVZ) cells, one of the putative cells of origin of GBM. We microdissected SVZ tissue from p53-null and wild-type adult mice, cultured cells in media supplemented with PDGF-AA, and assessed cell viability, proliferation, genome stability, and tumorigenicity. Counterintuitive to its canonical role as a growth factor, we observed abrupt and massive cell death in PDGF-AA: wild-type cells did not survive, whereas a small fraction of null cells evaded apoptosis. Surviving null cells displayed attenuated proliferation accompanied by whole chromosome gains and losses. After approximately 100 days in PDGF-AA, cells suddenly proliferated rapidly, acquired growth factor independence, and became tumorigenic in immune-competent mice. Transformed cells had an oligodendrocyte precursor-like lineage marker profile, were resistant to platelet derived growth factor receptor alpha inhibition, and harbored highly abnormal karyotypes similar to human GBM. This model associates genome instability in neural progenitor cells with chronic exposure to PDGF-AA and is the first to approximate the genomic landscape of human GBM and the first in which the earliest phases of the disease can be studied directly. © The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Citation

Alexandra K Bohm, Jessica DePetro, Carmen E Binding, Amanda Gerber, Nicholas Chahley, N Dan Berger, Mathaeus Ware, Kaitlin Thomas, U Senapathi, Shazreh Bukhari, Cindy Chen, Erin Chahley, Cameron Grisdale, Sam Lawn, Yaping Yu, Raymond Wong, Yaoqing Shen, Hiba Omairi, Reza Mirzaei, Nourah Alshatti, Haley Pedersen, Wee Yong, Samuel Weiss, Jennifer Chan, P J Cimino, John Kelly, Steve Jones, Eric Holland, Michael Blough, Gregory Cairncross. In vitro modeling of glioblastoma initiation using PDGF-AA and p53-null neural progenitors. Neuro-oncology. 2020 Aug 17;22(8):1150-1161

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PMID: 32296841

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