Summary
The molecular basis underlying Glioblastoma (GBM) heterogeneity and plasticity are not fully understood. Using transcriptomic data of patient-derived brain tumor stem cell lines (BTSCs), classified based on GBM-intrinsic signatures, we identify the AP-1 transcription factor FOSL1 as a master regulator of the mesenchymal (MES) subtype. We provide a mechanistic basis to the role of the Neurofibromatosis type 1 gene (NF1), a negative regulator of the RAS/MAPK pathway, in GBM mesenchymal transformation through the modulation of FOSL1 expression. Depletion of FOSL1 in NF1-mutant human BTSCs and Kras-mutant mouse neural stem cells results in loss of the mesenchymal gene signature, reduction in stem cell properties and in vivo tumorigenic potential. Our data demonstrate that FOSL1 controls GBM plasticity and aggressiveness in response to NF1 alterations.
Significance Glioblastoma (GBM) is a very heterogenous disease for which multiple transcriptional subtypes have been described. Among these subtypes, the Mesenchymal (MES) GBMs have the worst prognosis. Here we provide the first causal evidence linking Neurofibromatosis type 1 gene (NF1) signalling and the acquisition of a MES gene expression program through the regulation of the AP-1 transcription factor FOSL1. Using patient expression datasets, combined with in vitro and in vivo gain- and loss-of function mouse models, we show that FOSL1 is an important modulator of GBM that is required and sufficient for the activation of a MES program. Our work sheds light on the mechanisms that control the tumorigenicity of the most aggressive adult brain tumor type.