Identification of a Druggable Pathway Controlling Glioblastoma Invasiveness

Publication date: 5 July 2017
Source:Cell Reports, Volume 20, Issue 1
Author(s): Nora Pencheva, Mark C. de Gooijer, Daniel J. Vis, Lodewyk F.A. Wessels, Tom Würdinger, Olaf van Tellingen, René Bernards
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.

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Teaser

Pencheva et al. describe an ex vivo organotypic brain slice model of glioblastoma invasiveness. Using this model, the authors discover a pro-invasive network of extracellular matrix collagens that are transcriptionally repressed by interferon regulatory factor 3. Small-molecule targeting of casein kinase 2 inhibits invasion by activating interferon regulatory factor 3.


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