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

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 regul...

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Veröffentlicht in:eLife Jg. 10
Hauptverfasser: Marques, Carolina, Unterkircher, Thomas, Kroon, Paula, Oldrini, Barbara, Izzo, Annalisa, Dramaretska, Yuliia, Ferrarese, Roberto, Kling, Eva, Schnell, Oliver, Nelander, Sven, Wagner, Erwin F, Bakiri, Latifa, Gargiulo, Gaetano, Carro, Maria Stella, Squatrito, Massimo
Format: Journal Article
Sprache:Englisch
Veröffentlicht: England eLife Sciences Publications Ltd 17.08.2021
eLife Sciences Publications, Ltd
Schlagworte:
Activator protein 1
Brain cancer
Brain Neoplasms - genetics
Brain stem
Brain tumors
Cancer Biology
Cell cycle
Cell Line, Tumor
Classification
Datasets
FOSL1
FRA-1
GBM
Gene expression
Gene Expression Regulation, Neoplastic
Glioblastoma
Glioblastoma - genetics
Humans
MAP kinase
mesenchymal
Mesenchyme
Mutants
Mutation
Neoplastic Stem Cells - pathology
Neural stem cells
Neurofibromatosis
Neurofibromin 1
Neurofibromin 1 - genetics
Neurofibromin 1 - metabolism
NF1
Proto-Oncogene Proteins c-fos - genetics
Proto-Oncogene Proteins c-fos - metabolism
Stem cell transplantation
Stem cells
Transcription factors
Transcriptomics
Tumor cell lines
Tumors
FOSL1
mouse
GBM
mesenchymal
NF1
FRA-1
cancer biology
human
ISSN:2050-084X, 2050-084X
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Zusammenfassung: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.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
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ISSN:2050-084X
2050-084X
DOI:10.7554/eLife.64846