Integrative Modeling Reveals Annexin A2-mediated Epigenetic Control of Mesenchymal Glioblastoma.
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.
Sahlgrenska Cancer Center, Department of Pathology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
Teresia
T
Kling
Department of Neurosurgery, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Germany.
Roberto
R
Ferrarese
Department of Neurosurgery, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Germany; Faculty of Biology, Schnzlestrasse 1, University of Freiburg, D-79104 Freiburg, Germany.
Darren
D
Ó hAilín
Dept of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Rudbecklaboratoriet, SE-751 85 Uppsala, Sweden.
Patrik
P
Johansson
Department of Neurosurgery, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Germany.
Dieter Henrik
DH
Heiland
Department of Neurosurgery, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Germany.
Fangping
F
Dai
Department of Neurosurgery, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Germany.
Ioannis
I
Vasilikos
Department of Neurosurgery, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Germany.
Astrid
A
Weyerbrock
Mathematical Sciences, University of Gothenburg and Chalmers University of Technology, SE-412 96 Gothenburg, Sweden.
Rebecka
R
Jörnsten
Department of Neurosurgery, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Germany. Electronic address: maria.carro@uniklinik-freiburg.de.
Maria Stella
MS
Carro
Dept of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Rudbecklaboratoriet, SE-751 85 Uppsala, Sweden. Electronic address: sven.nelander@igp.uu.se.
Sven
S
Nelander
D000465:Algorithms; D017306:Annexin A2 / Q000235:genetics / Q000378:metabolism*; D014408:Biomarkers, Tumor; D045744:Cell Line, Tumor; D019295:Computational Biology / Q000379:methods; D019175:DNA Methylation; D030561:Databases, Nucleic Acid; D044127:Epigenesis, Genetic; D058750:Epithelial-Mesenchymal Transition; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D006801:Humans; D008637:Mesenchymoma / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D058977:Molecular Sequence Annotation; D060787:Neoplasm Grading; D014411:Neoplastic Stem Cells / Q000378:metabolism; D011379:Prognosis; D011401:Promoter Regions, Genetic
D017306:Annexin A2; D014408:Biomarkers, Tumor
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
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