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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 (Institutionen för matematiska vetenskaper, matematisk statistik) ; Maria Stella Carro ; Sven Nelander
EBioMedicine (2352-3964). Vol. 12 (2016), p. 72-85.
[Artikel, refereegranskad vetenskaplig]

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.

Nyckelord: Annexin A2; Brain tumor stem cells; Data integration; Epigenetic regulation; Glioblastoma; Master regulators of cancer cell phenotypes; Mesenchymal transformation; New methods for integrative data analysis; Partial correlation based networks; Spare inverse covariance selection

Denna post skapades 2016-12-29. Senast ändrad 2017-03-10.
CPL Pubid: 246536


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Institutioner (Chalmers)

Institutionen för matematiska vetenskaper, matematisk statistik (2005-2016)


Bioinformatik och systembiologi
Cancer och onkologi

Chalmers infrastruktur