Koessinger, D. et al. (2023) Glioblastoma extracellular vesicles influence glial cell hyaluronic acid deposition to promote invasiveness. Neuro-Oncology Advances, 5(1), vdad067. (doi: 10.1093/noajnl/vdad067) (PMID:37334166) (PMCID:PMC10276538)
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Abstract
Background. Infiltration of glioblastoma (GBM) throughout the brain leads to its inevitable recurrence following standard-of-care treatments, such as surgical resection, chemo- and radio-therapy. A deeper understanding of the mechanisms invoked by GMB to infiltrate the brain is needed to develop approaches to contain the disease and reduce recurrence. The aim of this study was to discover mechanisms through which extracellular vesicles (EVs) released by GBM influence the brain microenvironment to facilitate infiltration, and to determine how altered extracellular matrix (ECM) deposition by glial cells might contribute to this. Methods. CRISPR was used to delete genes, previously established to drive carcinoma invasiveness and EV production, from patient-derived primary and GBM cell lines. We purified and characterised EVs released by these cells, assessed their capacity to foster pro-migratory microenvironments in mouse brain slices, and evaluated the contribution made by astrocyte-derived extracellular matrix (ECM) to this. Finally, we determined how CRISPR-mediated deletion of genes, which we had found to control EV-mediated communication between GBM cells and astrocytes, influenced GBM infiltration when orthotopically injected into CD1-nude mice. Results. GBM cells expressing a p53 mutant (p53 273H) with established pro-invasive gain-of-function release EVs containing a sialomucin, podocalyxin (PODXL), which encourages astrocytes to deposit ECM with increased levels of hyaluronic acid (HA). This HA-rich ECM, in turn, promotes migration of GBM cells. Consistently, CRISPR-mediated deletion of PODXL opposes infiltration of GBM in vivo. Conclusions This work describes several key components of an EV-mediated mechanism though which GBM cells educate astrocytes to support infiltration of the surrounding healthy brain tissue. Conclusions. This work describes several key components of an EV-mediated mechanism though which GBM cells educate astrocytes to support infiltration of the surrounding healthy brain tissue.
| Item Type: | Articles |
|---|---|
| Additional Information: | Funding. This work was funded by Cancer Research UK (A18277), Breast Cancer Now (2019NovPR1268), and the Medical Research Council (MR/P01058X/1). We acknowledge the Cancer Research UK Glasgow Centre (C596/A18076) and the BSU facilities at the Cancer Research UK Beatson Institute (C596/A17196). |
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Novo, Dr David and Norman, Professor James and Birch, Dr Joanna and Stevenson, Mrs Katrina and Paschke, Dr Peggy and Koessinger, Dr Anna and Zerbst, Désirée and Neilson, Dr Matthew and Peters, Jasmine and Tait, Professor Stephen and Dutton, Ms Louise and Koessinger, Dr Dominik and Chalmers, Professor Anthony |
| Authors: | Koessinger, D., Novo, D., Koessinger, A., Campos, A., Peters, J., Dutton, L., Paschke, P., Zerbst, D., Moore, M., Mitchell, L., Neilson, M., Stevenson, K., Chalmers, A., Tait, S., Birch, J., and Norman, J. |
| College/School: | College of Medical Veterinary and Life Sciences College of Medical Veterinary and Life Sciences > School of Cancer Sciences |
| Journal Name: | Neuro-Oncology Advances |
| Publisher: | Oxford University Press |
| ISSN: | 2632-2498 |
| ISSN (Online): | 2632-2498 |
| Published Online: | 27 May 2023 |
| Copyright Holders: | Copyright © 2023 The Authors |
| First Published: | First published in Neuro-Oncology Advances 5(1):vdad067 |
| Publisher Policy: | Reproduced under a Creative Commons licence |
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