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

Autor:	Marques C; Seve Ballesteros Foundation Brain Tumor Group, Spanish National Cancer Research Centre, Madrid, Spain., Unterkircher T; Department of Neurosurgery, Faculty of Medicine Freiburg, Freiburg, Germany., Kroon P; Seve Ballesteros Foundation Brain Tumor Group, Spanish National Cancer Research Centre, Madrid, Spain., Oldrini B; Seve Ballesteros Foundation Brain Tumor Group, Spanish National Cancer Research Centre, Madrid, Spain., Izzo A; Department of Neurosurgery, Faculty of Medicine Freiburg, Freiburg, Germany., Dramaretska Y; Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany., Ferrarese R; Department of Neurosurgery, Faculty of Medicine Freiburg, Freiburg, Germany., Kling E; Department of Neurosurgery, Faculty of Medicine Freiburg, Freiburg, Germany., Schnell O; Department of Neurosurgery, Faculty of Medicine Freiburg, Freiburg, Germany., Nelander S; Dept of Immunology, Genetics and Pathology and Science for Life Laboratory, Uppsala University, Rudbecklaboratoriet, Uppsala, Sweden.; Science for Life Laboratory, Uppsala University, Rudbecklaboratoriet, Uppsala, Sweden., Wagner EF; Genes, Development, and Disease Group, Spanish National Cancer Research Centre, Madrid, Spain.; Laboratory Medicine Department, Medical University of Vienna, Vienna, Austria.; Dermatology Department, Medical University of Vienna, Vienna, Austria., Bakiri L; Genes, Development, and Disease Group, Spanish National Cancer Research Centre, Madrid, Spain.; Laboratory Medicine Department, Medical University of Vienna, Vienna, Austria., Gargiulo G; Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany., Carro MS; Department of Neurosurgery, Faculty of Medicine Freiburg, Freiburg, Germany., Squatrito M; Seve Ballesteros Foundation Brain Tumor Group, Spanish National Cancer Research Centre, Madrid, Spain.
Jazyk:	angličtina
Zdroj:	ELife [Elife] 2021 Aug 17; Vol. 10. Date of Electronic Publication: 2021 Aug 17.
DOI:	10.7554/eLife.64846
Abstrakt:	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. Competing Interests: CM, TU, PK, BO, AI, YD, RF, EK, OS, SN, EW, LB, GG, MC, MS No competing interests declared (© 2021, Marques et al.)
Databáze:	MEDLINE
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