NF1 regulates mesenchymal glioblastoma plasticity and aggressiveness through the AP-1 transcription factor FOSL1

Abstract

The molecular basis underlying glioblastoma (GBM) heterogeneity and plasticity is not fully understood. Using transcriptomic data of human patient-derived brain tumor stem cell lines (BTSCs), classified based on GBM-intrinsic signatures, we identify the AP-1 transcription factor <i>FOSL1</i> as a key regulator of the mesenchymal (MES) subtype. We provide a mechanistic basis to the role of the neurofibromatosis type 1 gene (<i>NF1</i>), a negative regulator of the RAS/MAPK pathway, in GBM mesenchymal transformation through the modulation of <i>FOSL1</i> expression. Depletion of <i>FOSL1</i> in <i>NF1</i>-mutant human BTSCs and <i>Kras</i>-mutant mouse neural stem cells results in loss of the mesenchymal gene signature and reduction in stem cell properties and in vivo tumorigenic potential. Our data demonstrate that <i>FOSL1</i> controls GBM plasticity and aggressiveness in response to <i>NF1</i> alterations.