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

Journal article
Authors Teresia Kling
R. Ferrarese
D. O. Ailin
P. Johansson
D. H. Heiland
F. P. Dai
I. Vasilikos
A. Weyerbrock
Rebecka Jörnsten
M. S. Carro
S. Nelander
Published in Ebiomedicine
Volume 12
Pages 72-85
ISSN 2352-3964
Publication year 2016
Published at Department of Mathematical Sciences, Mathematical Statistics
Sahlgrenska Cancer Center
Pages 72-85
Language en
Keywords Glioblastoma, New methods for integrative data analysis, Mesenchymal transformation, Partial correlation based networks, Brain tumor stem cells, Annexin A2, Master regulators of cancer cell phenotypes, Epigenetic regulation, Data integration, Spare inve, alternatively spliced segment, human glioma-cells, malignant glioma, brain-tumors, cancer cells, tenascin-c, in-vitro, a2, expression, subtypes, General & Internal Medicine, ung cy, 1994, journal of cell biology, v126, p539
Subject categories Cancer and Oncology

Abstract

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. (C) 2016 Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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