A novel integrative network model identifies ANXA2 as an epigenetically controlled driver of mesenchymal signature in glioblastoma.
Roberto Ferrarese, Universitätsklinikum Freiburg Neuroonkologie Breisacher Straße 64 -79106- Freiburg; Teresia Kling, University of Gothenburg Sahlgrenska Cancer Center Vaestra Goetaland Sweden; Darren Ó hAilín, Universitätsklinikum Freiburg Neuroonkologie Breisacher Straße 64 -79106- Freiburg; Patrik Johansson, Uppsala Universitet Department of Immunology Genetics and Pathology Rudbecklaboratoriet 751 85 Uppsala; Sven Nelander, Uppsala Universitet Department of Immunology Genetics and Pathology Rudbecklaboratoriet 751 85 Uppsala; Maria Stella Carro, Universitätsklinikum Freiburg Neuroonkologie Breisacher Straße 64 -79106- Freiburg
A novel integrated modeling approach to detect genomic and epigenetic correlations to mRNA changes in GBM revealed a robust link between ANXA2 expression and GBM mesenchymal signature, and between ANXA2 promoter methylation and patient survival; ANXA2 expression and promoter methylation were also negatively correlated to each other. This finding prompted further investigation of ANXA2’s role in determining the aggressive mesenchymal phenotype. Analysis of GBM tissue samples from both public databases and in-house materials confirmed that ANXA2 expression was inversely correlated with promoter methylation, and positively correlated with tumor grade, supporting the model prediction that ANXA2 expression is epigenetically controlled. ANXA2 knockdown in patient-derived cancer stem cell lines decreased cell proliferation and invasiveness, and induced a global transcriptional shift, downregulating the expression of mesenchymal signature genes. Although no effect on global DNA methylation was observed, upon ANXA2 knockdown, cancer stem cells showed an enriched expression of those genes which are expressed by G-CIMP+ tumors, suggesting that ANXA2 silencing might transcriptionally mimic IDH1 mutation-driven hypermethylator phenotype, associated with improved prognosis in GBM. In summary, a novel data integrative strategy has been exploited to identify a causative link between epigenetic regulation of ANXA2 promoter and the establishment of the aggressive mesenchymal phenotype in GBM.Format: Oral communication