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Cell Rep. 2017 Jul 5;20(1):48-60. doi: 10.1016/j.celrep.2017.06.036.

Identification of a Druggable Pathway Controlling Glioblastoma Invasiveness.

Author information

1
Division of Molecular Carcinogenesis and Cancer Genomics Center Netherlands, the Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
2
Division of Pharmacology, the Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
3
Department of Neurosurgery, VU University Medical Center, Cancer Center Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, the Netherlands.
4
Division of Pharmacology, the Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands. Electronic address: o.v.tellingen@nki.nl.
5
Division of Molecular Carcinogenesis and Cancer Genomics Center Netherlands, the Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands. Electronic address: r.bernards@nki.nl.

Abstract

Diffuse and uncontrollable brain invasion is a hallmark of glioblastoma (GBM), but its mechanism is understood poorly. We developed a 3D ex vivo organotypic model to study GBM invasion. We demonstrate that invading GBM cells upregulate a network of extracellular matrix (ECM) components, including multiple collagens, whose expression correlates strongly with grade and clinical outcome. We identify interferon regulatory factor 3 (IRF3) as a transcriptional repressor of ECM factors and show that IRF3 acts as a suppressor of GBM invasion. Therapeutic activation of IRF3 by inhibiting casein kinase 2 (CK2)-a negative regulator of IRF3-downregulated the expression of ECM factors and suppressed GBM invasion in ex vivo and in vivo models across a panel of patient-derived GBM cell lines representative of the main molecular GBM subtypes. Our data provide mechanistic insight into the invasive capacity of GBM tumors and identify a potential therapy to inhibit GBM invasion.

KEYWORDS:

casein kinase 2; collagen; extracellular matrix; glioblastoma; interferon regulatory factor 3; invasion

PMID:
28683323
DOI:
10.1016/j.celrep.2017.06.036
[Indexed for MEDLINE]
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