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 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.

Identification of MAD2L1 as a Potential Biomarker in Hepatocellular Carcinoma via Comprehensive Bioinformatics Analysis

“…To narrow down the number of “candidate” DEGs and determine potential “key” genes for HCC development [ 30 , 31 , 33 , 34 ], a PPI network of 145 DEGs was constructed to visualize the relationships between genes, followed by functional analysis. Based on their connectivity level, the top ten hub genes identified included CCNB1, MAD2L1, CCNA2, AURKA, ZWINT, HMMR, TPX2, EZH2, and OIP5.…”

Role of the Transcription Factor FOSL1 in Organ Development and Tumorigenesis

“…The latter is accompanied by altering the shape of tumor cells and impairing their anchorage. For instance, FOSL1 accumulation in non-tumorigenic glioma cell lines in vitro confers tumorigenicity [87]. On the contrary, diminishing the FOSL1 level by 80% restores cell morphology, impairs cell motility, and normalizes the metabolic processes [88].…”

Neurofibromatosis Type 1 Gene Alterations Define Specific Features of a Subset of Glioblastomas

“…Moreover, immunotherapies seem to be not only a promising strategy for mesenchymal gliomas, but they are also an important treatment option for NF1-related melanomas, lung carcinomas, or MPNST. Recently, loss of NF1 was shown to modulate FOS like 1, AP-1 transcription factor subunit (FOSL1) expression, which is a key regulator for stemness, mesenchymal shift, and plasticity [ 113 ]. Transcription factor FOSL1 is overexpressed in cancer and associated with worse outcomes and EMT as well as with glioma malignancy [ 113 ].…”

“…Recently, loss of NF1 was shown to modulate FOS like 1, AP-1 transcription factor subunit (FOSL1) expression, which is a key regulator for stemness, mesenchymal shift, and plasticity [ 113 ]. Transcription factor FOSL1 is overexpressed in cancer and associated with worse outcomes and EMT as well as with glioma malignancy [ 113 ]. The authors demonstrated that FOSL1 depletion in NF1 mutant human brain tumour stem cells and KRAS mutant mouse neural stem cells resulted in the loss of the MES signature and a reduction in stem cell properties.…”

“…The authors demonstrated that FOSL1 depletion in NF1 mutant human brain tumour stem cells and KRAS mutant mouse neural stem cells resulted in the loss of the MES signature and a reduction in stem cell properties. They first proved that NF1 mutations act via the NF1–MAPK–FOSL1 axis in MES gliomas as they increase FOSL1 RNA and protein expression and therefore activate the expression of the MES gene signature and inhibit the non-MES gene signature [ 113 ].…”