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Glioblastoma extracellular vesicles influence glial cell hyaluronic acid deposition to promote invasiveness

BACKGROUND: Infiltration of glioblastoma (GBM) throughout the brain leads to its inevitable recurrence following standard-of-care treatments, such as surgical resection, chemo-, and radiotherapy. A deeper understanding of the mechanisms invoked by GBM to infiltrate the brain is needed to develop app...

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Autores principales: Koessinger, Dominik, Novo, David, Koessinger, Anna, Campos, America, Peters, Jasmine, Dutton, Louise, Paschke, Peggy, Zerbst, Désirée, Moore, Madeleine, Mitchell, Louise, Neilson, Matthew, Stevenson, Katrina, Chalmers, Anthony, Tait, Stephen, Birch, Joanna, Norman, Jim
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10276538/
https://www.ncbi.nlm.nih.gov/pubmed/37334166
http://dx.doi.org/10.1093/noajnl/vdad067
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author Koessinger, Dominik
Novo, David
Koessinger, Anna
Campos, America
Peters, Jasmine
Dutton, Louise
Paschke, Peggy
Zerbst, Désirée
Moore, Madeleine
Mitchell, Louise
Neilson, Matthew
Stevenson, Katrina
Chalmers, Anthony
Tait, Stephen
Birch, Joanna
Norman, Jim
author_facet Koessinger, Dominik
Novo, David
Koessinger, Anna
Campos, America
Peters, Jasmine
Dutton, Louise
Paschke, Peggy
Zerbst, Désirée
Moore, Madeleine
Mitchell, Louise
Neilson, Matthew
Stevenson, Katrina
Chalmers, Anthony
Tait, Stephen
Birch, Joanna
Norman, Jim
author_sort Koessinger, Dominik
collection PubMed
description BACKGROUND: Infiltration of glioblastoma (GBM) throughout the brain leads to its inevitable recurrence following standard-of-care treatments, such as surgical resection, chemo-, and radiotherapy. A deeper understanding of the mechanisms invoked by GBM 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 characterized 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 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(R273H)) 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.
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spelling pubmed-102765382023-06-18 Glioblastoma extracellular vesicles influence glial cell hyaluronic acid deposition to promote invasiveness Koessinger, Dominik Novo, David Koessinger, Anna Campos, America Peters, Jasmine Dutton, Louise Paschke, Peggy Zerbst, Désirée Moore, Madeleine Mitchell, Louise Neilson, Matthew Stevenson, Katrina Chalmers, Anthony Tait, Stephen Birch, Joanna Norman, Jim Neurooncol Adv Basic and Translational Investigations BACKGROUND: Infiltration of glioblastoma (GBM) throughout the brain leads to its inevitable recurrence following standard-of-care treatments, such as surgical resection, chemo-, and radiotherapy. A deeper understanding of the mechanisms invoked by GBM 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 characterized 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 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(R273H)) 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. Oxford University Press 2023-05-27 /pmc/articles/PMC10276538/ /pubmed/37334166 http://dx.doi.org/10.1093/noajnl/vdad067 Text en © The Author(s) 2023. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Basic and Translational Investigations
Koessinger, Dominik
Novo, David
Koessinger, Anna
Campos, America
Peters, Jasmine
Dutton, Louise
Paschke, Peggy
Zerbst, Désirée
Moore, Madeleine
Mitchell, Louise
Neilson, Matthew
Stevenson, Katrina
Chalmers, Anthony
Tait, Stephen
Birch, Joanna
Norman, Jim
Glioblastoma extracellular vesicles influence glial cell hyaluronic acid deposition to promote invasiveness
title Glioblastoma extracellular vesicles influence glial cell hyaluronic acid deposition to promote invasiveness
title_full Glioblastoma extracellular vesicles influence glial cell hyaluronic acid deposition to promote invasiveness
title_fullStr Glioblastoma extracellular vesicles influence glial cell hyaluronic acid deposition to promote invasiveness
title_full_unstemmed Glioblastoma extracellular vesicles influence glial cell hyaluronic acid deposition to promote invasiveness
title_short Glioblastoma extracellular vesicles influence glial cell hyaluronic acid deposition to promote invasiveness
title_sort glioblastoma extracellular vesicles influence glial cell hyaluronic acid deposition to promote invasiveness
topic Basic and Translational Investigations
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10276538/
https://www.ncbi.nlm.nih.gov/pubmed/37334166
http://dx.doi.org/10.1093/noajnl/vdad067
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