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Interferon-β exposure induces a fragile glioblastoma stem cell phenotype with a transcriptional profile of reduced migratory and MAPK pathway activity


Lohmann, Birthe; Silginer, Manuela; Picard, Daniel; Schneider, Hannah; Remke, Marc; Roth, Patrick; Reifenberger, Guido; Weller, Michael (2020). Interferon-β exposure induces a fragile glioblastoma stem cell phenotype with a transcriptional profile of reduced migratory and MAPK pathway activity. Neuro-oncology advances, 2(1):vdaa043.

Abstract

Background: Type I interferons (IFN-α/β) are cytokines that are typically expressed in response to double-stranded RNA associated with viral infections. Glioblastomas are the most common malignant primary brain tumors, characterized by an infiltrative growth pattern and prominent angiogenic activity, and thought to be maintained by a subpopulation of glioma-initiating (stem-like) cells (GICs). The growth of human GIC lines is highly sensitive to IFN-β.
Methods: Repetitive pulse stimulation with IFN-β1a (IS) was used to generate IS sublines that had acquired resistance to IFN-β-induced suppression of sphere formation. These cell lines were characterized by analyses of type 1 IFN signaling, growth patterns, and transcriptomic profiles.
Results: Here we report that repetitive IFN-β1a stimulation (IS) induces a stable phenotype (referred to as IS) at the level of maintaining sphere formation, although classical IFN signaling defined by the expression of both IFN receptors, myxovirus resistance protein A (MxA) accumulation, and STAT1 induction is unaffected. Furthermore, this stably altered IS phenotype is characterized by constitutively decreased sphere formation capacity and morphological features of senescence and autophagy. Transcriptional profiling reveals increased type I IFN signaling in these IS cells, but decreased expression of genes involved in receptor signaling and cell migration.
Conclusions: Altogether, these data suggest a role for promoting IFN-β signaling in glioblastoma and might provide clues to design future therapeutic approaches.

Abstract

Background: Type I interferons (IFN-α/β) are cytokines that are typically expressed in response to double-stranded RNA associated with viral infections. Glioblastomas are the most common malignant primary brain tumors, characterized by an infiltrative growth pattern and prominent angiogenic activity, and thought to be maintained by a subpopulation of glioma-initiating (stem-like) cells (GICs). The growth of human GIC lines is highly sensitive to IFN-β.
Methods: Repetitive pulse stimulation with IFN-β1a (IS) was used to generate IS sublines that had acquired resistance to IFN-β-induced suppression of sphere formation. These cell lines were characterized by analyses of type 1 IFN signaling, growth patterns, and transcriptomic profiles.
Results: Here we report that repetitive IFN-β1a stimulation (IS) induces a stable phenotype (referred to as IS) at the level of maintaining sphere formation, although classical IFN signaling defined by the expression of both IFN receptors, myxovirus resistance protein A (MxA) accumulation, and STAT1 induction is unaffected. Furthermore, this stably altered IS phenotype is characterized by constitutively decreased sphere formation capacity and morphological features of senescence and autophagy. Transcriptional profiling reveals increased type I IFN signaling in these IS cells, but decreased expression of genes involved in receptor signaling and cell migration.
Conclusions: Altogether, these data suggest a role for promoting IFN-β signaling in glioblastoma and might provide clues to design future therapeutic approaches.

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Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Neurology
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:2020
Deposited On:17 Dec 2020 17:28
Last Modified:01 Jan 2021 20:51
Publisher:Oxford University Press
ISSN:2632-2498
Additional Information:This is a pre-copy-editing, author-produced PDF of an article accepted for publication in Neuro-oncology advancesfollowing peer review. The definitive publisher-authenticated version Lohmann B, Silginer M, Picard D, Schneider H, Remke M, Roth P, Reifenberger G, Weller M. Interferon-β exposure induces a fragile glioblastoma stem cell phenotype with a transcriptional profile of reduced migratory and MAPK pathway activity. Neurooncol Adv. 2020 Mar 28;2(1):vdaa043. doi: 10.1093/noajnl/vdaa043. is available online at: https://academic.oup.com/noa/article/2/1/vdaa043/5812985
OA Status:Gold
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1093/noajnl/vdaa043
PubMed ID:32642697

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