A syngeneic glioblastoma mouse model with mesenchymal hallmarks.

Abstract

Primary brain cancer has a poor prognosis, and especially glioblastoma (GBM) patients have a median survival of only 15 months. The standard of care treatment has not changed in the last 20 years, highlighting the need for research and development, which would warrant the need for better model systems. Mouse models of GBM allow researchers to address biological questions in a physiological setting that resembles human glioma. Orthotopic grafting of glioma cells has shown a lack of tumor-parenchyma interaction, limiting the model's relevance. In this study, we propagated glioma cells from a CRISPR-induced GBM with mutations in Nf1, Trp53, and Pten. Of the six derived cell lines, two could develop a tumor when syngeneically orthotopically grafted. The AMG5 line resembled the parental tumor with a diffuse tumor border, neovascularization, low immune cell infiltration, and a dense tumor core. Furthermore, this GBM had features of a mesenchymal subtype with decreased expression of Sox2 and Olig2 but contains macrophages in the tumor stroma. The humane endpoint was reached after 6-8 weeks, allowing for timely treatment intervention and monitoring of tumor progression. Therefore, the AMG5 line provides a new tool in glioma research by generating reproducible GBM with features of mesenchymal subtype to address emerging questions and to better understand GBM development.