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Fishing for contact: Modeling perivascular glioma invasion in the zebrafish brain

View ORCID ProfileRobyn A. Umans, Mattie ten Kate, Carolyn Pollock, View ORCID ProfileHarald Sontheimer
doi: https://doi.org/10.1101/2020.08.15.252544
Robyn A. Umans
1Center for Glial Biology in Health, Disease, and Cancer, The Fralin Biomedical Research Institute at VTC, Roanoke, VA, 24016, USA
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Mattie ten Kate
2School of Neuroscience, Sandy Hall, 210 Drillfield Dr.,Virginia Tech, Blacksburg, VA, 24061, USA
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Carolyn Pollock
2School of Neuroscience, Sandy Hall, 210 Drillfield Dr.,Virginia Tech, Blacksburg, VA, 24061, USA
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Harald Sontheimer
1Center for Glial Biology in Health, Disease, and Cancer, The Fralin Biomedical Research Institute at VTC, Roanoke, VA, 24016, USA
2School of Neuroscience, Sandy Hall, 210 Drillfield Dr.,Virginia Tech, Blacksburg, VA, 24061, USA
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  • For correspondence: sontheim@vt.edu
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Abstract

Glioblastoma multiforme (GBM) is a highly invasive, central nervous system (CNS) cancer for which there is no a cure. Invading tumor cells evade treatment, limiting the efficacy of the current standard of care regimen. Understanding the underlying invasive behaviors that support tumor growth may allow for generation of novel GBM therapies. Zebrafish (Danio rerio) are attractive for genetics and live imaging, and have in recent years, emerged as a model system suitable for cancer biology research. While other groups have studied CNS tumors using zebrafish, few have concentrated on the invasive behaviors supporting the development of these diseases. Previous studies demonstrated that one of the main mechanisms of GBM invasion is perivascular invasion, i.e. single tumor cell migration along blood vessels. Here, we characterize phenotypes, methodology, and potential therapeutic avenues for utilizing zebrafish to model perivascular GBM invasion. Using patient derived xenolines or an adherent cell line, we demonstrate tumor expansion within the zebrafish brain. Within 24 hours post-intracranial injection, D54-MG-tdTomato glioma cells produce finger-like projections along the zebrafish brain vasculature. As few as 25 GBM cells were sufficient to promote single cell vessel co-option. Of note, these tumor-vessel interactions are CNS specific, and do not occur on pre-existing blood vessels when injected into the animal’s peripheral tissue. Tumor-vessel interactions increase over time and can be pharmacologically disrupted through inhibition of Wnt signaling. Therefore, zebrafish serve as a favorable model system to study perivascular glioma invasion, one of the deadly characteristics that make GBM so difficult to treat.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • Figures 1 and 6 revised. Results updated to clarify the importance of cell number injected. Discussion updated to clarify importance of extracellular matrix environment and use of XAV939.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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Posted November 21, 2020.
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Fishing for contact: Modeling perivascular glioma invasion in the zebrafish brain
Robyn A. Umans, Mattie ten Kate, Carolyn Pollock, Harald Sontheimer
bioRxiv 2020.08.15.252544; doi: https://doi.org/10.1101/2020.08.15.252544
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Fishing for contact: Modeling perivascular glioma invasion in the zebrafish brain
Robyn A. Umans, Mattie ten Kate, Carolyn Pollock, Harald Sontheimer
bioRxiv 2020.08.15.252544; doi: https://doi.org/10.1101/2020.08.15.252544

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