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Identifying conserved molecular targets required for cell migration of glioblastoma cancer stem cells

Glioblastoma (GBM) is the most prevalent primary malignant brain tumor and is associated with extensive tumor cell infiltration into the adjacent brain parenchyma. However, there are limited targeted therapies that address this disease hallmark. While the invasive capacity of self-renewing cancer st...

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Autores principales: Volovetz, Josephine, Berezovsky, Artem D., Alban, Tyler, Chen, Yujun, Lauko, Adam, Aranjuez, George F., Burtscher, Ashley, Shibuya, Kelly, Silver, Daniel J., Peterson, John, Manor, Danny, McDonald, Jocelyn A., Lathia, Justin D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7044427/
https://www.ncbi.nlm.nih.gov/pubmed/32102991
http://dx.doi.org/10.1038/s41419-020-2342-2
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author Volovetz, Josephine
Berezovsky, Artem D.
Alban, Tyler
Chen, Yujun
Lauko, Adam
Aranjuez, George F.
Burtscher, Ashley
Shibuya, Kelly
Silver, Daniel J.
Peterson, John
Manor, Danny
McDonald, Jocelyn A.
Lathia, Justin D.
author_facet Volovetz, Josephine
Berezovsky, Artem D.
Alban, Tyler
Chen, Yujun
Lauko, Adam
Aranjuez, George F.
Burtscher, Ashley
Shibuya, Kelly
Silver, Daniel J.
Peterson, John
Manor, Danny
McDonald, Jocelyn A.
Lathia, Justin D.
author_sort Volovetz, Josephine
collection PubMed
description Glioblastoma (GBM) is the most prevalent primary malignant brain tumor and is associated with extensive tumor cell infiltration into the adjacent brain parenchyma. However, there are limited targeted therapies that address this disease hallmark. While the invasive capacity of self-renewing cancer stem cells (CSCs) and their non-CSC progeny has been investigated, the mode(s) of migration used by CSCs during invasion is currently unknown. Here we used time-lapse microscopy to evaluate the migratory behavior of CSCs, with a focus on identifying key regulators of migration. A head-to-head migration assay demonstrated that CSCs are more invasive than non-CSCs. Time-lapse live cell imaging further revealed that GBM patient-derived CSC models either migrate in a collective manner or in a single cell fashion. To uncover conserved molecular regulators responsible for collective cell invasion, we utilized the genetically tractable Drosophila border cell collective migration model. Candidates for functional studies were generated using results from a targeted Drosophila genetic screen followed by gene expression analysis of the human homologs in GBM tumors and associated GBM patient prognosis. This strategy identified the highly conserved small GTPase, Rap1a, as a potential regulator of cell invasion. Alteration of Rap1a activity impaired the forward progress of Drosophila border cells during development. Rap1a expression was elevated in GBM and associated with higher tumor grade. Functionally, the levels of activated Rap1a impacted CSC migration speed out of spheres onto extracellular matrix. The data presented here demonstrate that CSCs are more invasive than non-CSCs, are capable of both collective and single cell migration, and express conserved genes that are required for migration and invasion. Using this integrated approach, we identified a new role for Rap1a in the migration of GBM CSCs.
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spelling pubmed-70444272020-03-04 Identifying conserved molecular targets required for cell migration of glioblastoma cancer stem cells Volovetz, Josephine Berezovsky, Artem D. Alban, Tyler Chen, Yujun Lauko, Adam Aranjuez, George F. Burtscher, Ashley Shibuya, Kelly Silver, Daniel J. Peterson, John Manor, Danny McDonald, Jocelyn A. Lathia, Justin D. Cell Death Dis Article Glioblastoma (GBM) is the most prevalent primary malignant brain tumor and is associated with extensive tumor cell infiltration into the adjacent brain parenchyma. However, there are limited targeted therapies that address this disease hallmark. While the invasive capacity of self-renewing cancer stem cells (CSCs) and their non-CSC progeny has been investigated, the mode(s) of migration used by CSCs during invasion is currently unknown. Here we used time-lapse microscopy to evaluate the migratory behavior of CSCs, with a focus on identifying key regulators of migration. A head-to-head migration assay demonstrated that CSCs are more invasive than non-CSCs. Time-lapse live cell imaging further revealed that GBM patient-derived CSC models either migrate in a collective manner or in a single cell fashion. To uncover conserved molecular regulators responsible for collective cell invasion, we utilized the genetically tractable Drosophila border cell collective migration model. Candidates for functional studies were generated using results from a targeted Drosophila genetic screen followed by gene expression analysis of the human homologs in GBM tumors and associated GBM patient prognosis. This strategy identified the highly conserved small GTPase, Rap1a, as a potential regulator of cell invasion. Alteration of Rap1a activity impaired the forward progress of Drosophila border cells during development. Rap1a expression was elevated in GBM and associated with higher tumor grade. Functionally, the levels of activated Rap1a impacted CSC migration speed out of spheres onto extracellular matrix. The data presented here demonstrate that CSCs are more invasive than non-CSCs, are capable of both collective and single cell migration, and express conserved genes that are required for migration and invasion. Using this integrated approach, we identified a new role for Rap1a in the migration of GBM CSCs. Nature Publishing Group UK 2020-02-26 /pmc/articles/PMC7044427/ /pubmed/32102991 http://dx.doi.org/10.1038/s41419-020-2342-2 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Volovetz, Josephine
Berezovsky, Artem D.
Alban, Tyler
Chen, Yujun
Lauko, Adam
Aranjuez, George F.
Burtscher, Ashley
Shibuya, Kelly
Silver, Daniel J.
Peterson, John
Manor, Danny
McDonald, Jocelyn A.
Lathia, Justin D.
Identifying conserved molecular targets required for cell migration of glioblastoma cancer stem cells
title Identifying conserved molecular targets required for cell migration of glioblastoma cancer stem cells
title_full Identifying conserved molecular targets required for cell migration of glioblastoma cancer stem cells
title_fullStr Identifying conserved molecular targets required for cell migration of glioblastoma cancer stem cells
title_full_unstemmed Identifying conserved molecular targets required for cell migration of glioblastoma cancer stem cells
title_short Identifying conserved molecular targets required for cell migration of glioblastoma cancer stem cells
title_sort identifying conserved molecular targets required for cell migration of glioblastoma cancer stem cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7044427/
https://www.ncbi.nlm.nih.gov/pubmed/32102991
http://dx.doi.org/10.1038/s41419-020-2342-2
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