Abstract
BACKGROUND: Meningioma is the most frequent primary intracranial tumour. Surgical resection remains the main therapeutic option as pharmacological intervention is still hampered by the poor knowledge of the molecular signature of these tumours MATERIAL AND METHODS: In order to elucidate the proteomic profiling of meningiomas and identify proteins involved in their pathogenesis, we completed a comparative mass spectrometry analysis of meningioma tissue of all WHO grades, analysing global proteins, phosphoproteins and phosphopeptides. We performed differential expression analyses and functional annotation studies to identify commonly upregulated proteins and phosphoprotein in all grades of meningioma compared to meningeal tissue as well as grade-specific candidates relevant for tumour progression. Top candidates werevalidated by Western blotting and immunohistochemistry in an additional sample set RESULTS: We confirmed significant overexpression of proteins including EGFR, STAT2 and CKAP4 across all grades, as well as the aberrant activation of the downstream PI3K/AKT pathway, which seems differential between grades. Further, we validated upregulation in all grades of the total and activated phosphorylated form of the NIMArelated kinase, NEK9, involved in mitotic progression. Novel proteins identified in meningioma and validated as commonly overexpressed in all grades were the nuclear proto-oncogene SET and the splicing factor SF2/ASF, while another newly identified protein that was specific for higher grades was hexokinase-2, involved in cellular metabolism CONCLUSION: Overall, we generated a proteomic thesaurus of meningiomas in order to decipher aberrantly expressed proteins and activated pathways; this body of knowledge will eventually lead to the identification of relevant biomarkers and therapeutic targets.