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

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Item Type:

Article

Title:

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

Creators Name:

Marques, C. and Unterkircher, T. and Kroon, P. and Oldrini, B. and Izzo, A. and Dramaretska, Y. and Ferrarese, R. and Kling, E. and Schnell, O. and Nelander, S. and Wagner, E.F. and Bakiri, L. and Gargiulo, G. and Carro, M.S. and Squatrito, M.

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 FOSL1 as a key 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 and 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.

Keywords:

Brain Neoplasms, Glioblastoma, Neoplastic Gene Expression Regulation, Neoplastic Stem Cells, Neurofibromin 1, Proto-Oncogene Proteins c-fos, Tumor Cell Line

Source:

eLife

ISSN:

2050-084X

Publisher:

eLife Sciences Publications

Volume:

Page Range:

e64846

Date:

17 August 2021

Official Publication: