Integrative Modeling Reveals Annexin A2-mediated Epigenetic Control of Mesenchymal Glioblastoma

Teresia Kling; Roberto Ferrarese; Darren Ó hAilín; Patrik Johansson; Dieter Henrik Heiland; Fangping Dai; Ioannis Vasilikos; Astrid Weyerbrock; Rebecka Jörnsten; Maria Stella Carro; Sven Nelander

doi:10.1016/j.ebiom.2016.08.050

Integrative Modeling Reveals Annexin A2-mediated Epigenetic Control of Mesenchymal Glioblastoma
Journal article, 2016

Glioblastomas are characterized by transcriptionally distinct subtypes, but despite possible clinical relevance, their regulation remains poorly understood. The commonly used molecular classification systems for GBM all identify a subtype with high expression of mesenchymal marker transcripts, strongly associated with invasive growth. We used a comprehensive data-driven network modeling technique (augmented sparse inverse covariance selection, aSICS) to define separate genomic, epigenetic, and transcriptional regulators of glioblastoma subtypes. Our model identified Annexin A2 (ANXA2) as a novel methylation-controlled positive regulator of the mesenchymal subtype. Subsequent evaluation in two independent cohorts established ANXA2 expression as a prognostic factor that is dependent on ANXA2 promoter methylation. ANXA2 knockdown in primary glioblastoma stem cell-like cultures suppressed known mesenchymal master regulators, and abrogated cell proliferation and invasion. Our results place ANXA2 at the apex of a regulatory cascade that determines glioblastoma mesenchymal transformation and validate aSICS as a general methodology to uncover regulators of cancer subtypes.

Epigenetic regulation

Brain tumor stem cells

New methods for integrative data analysis

Data integration

Master regulators of cancer cell phenotypes

Mesenchymal transformation

Spare inverse covariance selection

Glioblastoma

Partial correlation based networks

Annexin A2