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C3G downregulation induces the acquisition of a mesenchymal phenotype that enhances aggressiveness of glioblastoma cells

Glioblastoma (GBM) is the most aggressive tumor from the central nervous system (CNS). The current lack of efficient therapies makes essential to find new treatment strategies. C3G, a guanine nucleotide exchange factor for some Ras proteins, plays a dual role in cancer, but its function in GBM remai...

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Autores principales: Manzano, Sara, Gutierrez-Uzquiza, Alvaro, Bragado, Paloma, Sequera, Celia, Herranz, Óscar, Rodrigo-Faus, María, Jauregui, Patricia, Morgner, Stephanie, Rubio, Ignacio, Guerrero, Carmen, Porras, Almudena
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8024353/
https://www.ncbi.nlm.nih.gov/pubmed/33824275
http://dx.doi.org/10.1038/s41419-021-03631-w
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author Manzano, Sara
Gutierrez-Uzquiza, Alvaro
Bragado, Paloma
Sequera, Celia
Herranz, Óscar
Rodrigo-Faus, María
Jauregui, Patricia
Morgner, Stephanie
Rubio, Ignacio
Guerrero, Carmen
Porras, Almudena
author_facet Manzano, Sara
Gutierrez-Uzquiza, Alvaro
Bragado, Paloma
Sequera, Celia
Herranz, Óscar
Rodrigo-Faus, María
Jauregui, Patricia
Morgner, Stephanie
Rubio, Ignacio
Guerrero, Carmen
Porras, Almudena
author_sort Manzano, Sara
collection PubMed
description Glioblastoma (GBM) is the most aggressive tumor from the central nervous system (CNS). The current lack of efficient therapies makes essential to find new treatment strategies. C3G, a guanine nucleotide exchange factor for some Ras proteins, plays a dual role in cancer, but its function in GBM remains unknown. Database analyses revealed a reduced C3G mRNA expression in GBM patient samples. C3G protein levels were also decreased in a panel of human GBM cell lines as compared to astrocytes. Based on this, we characterized C3G function in GBM using in vitro and in vivo human GBM models. We report here that C3G downregulation promoted the acquisition of a more mesenchymal phenotype that enhanced the migratory and invasive capacity of GBM cells. This facilitates foci formation in anchorage-dependent and -independent growth assays and the generation of larger tumors in xenografts and chick chorioallantoic membrane (CAM) assays, but with a lower cell density, as proliferation was reduced. Mechanistically, C3G knock-down impairs EGFR signaling by reducing cell surface EGFR through recycling inhibition, while upregulating the activation of several other receptor tyrosine kinases (RTKs) that might promote invasion. In particular, FGF2, likely acting through FGFR1, promoted invasion of C3G-silenced GBM cells. Moreover, ERKs mediate this invasiveness, both in response to FGF2- and serum-induced chemoattraction. In conclusion, our data show the distinct dependency of GBM tumors on C3G for EGF/EGFR signaling versus other RTKs, suggesting that assessing C3G levels may discriminate GBM patient responders to different RTK inhibition protocols. Hence, patients with a low C3G expression might not respond to EGFR inhibitors.
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spelling pubmed-80243532021-04-21 C3G downregulation induces the acquisition of a mesenchymal phenotype that enhances aggressiveness of glioblastoma cells Manzano, Sara Gutierrez-Uzquiza, Alvaro Bragado, Paloma Sequera, Celia Herranz, Óscar Rodrigo-Faus, María Jauregui, Patricia Morgner, Stephanie Rubio, Ignacio Guerrero, Carmen Porras, Almudena Cell Death Dis Article Glioblastoma (GBM) is the most aggressive tumor from the central nervous system (CNS). The current lack of efficient therapies makes essential to find new treatment strategies. C3G, a guanine nucleotide exchange factor for some Ras proteins, plays a dual role in cancer, but its function in GBM remains unknown. Database analyses revealed a reduced C3G mRNA expression in GBM patient samples. C3G protein levels were also decreased in a panel of human GBM cell lines as compared to astrocytes. Based on this, we characterized C3G function in GBM using in vitro and in vivo human GBM models. We report here that C3G downregulation promoted the acquisition of a more mesenchymal phenotype that enhanced the migratory and invasive capacity of GBM cells. This facilitates foci formation in anchorage-dependent and -independent growth assays and the generation of larger tumors in xenografts and chick chorioallantoic membrane (CAM) assays, but with a lower cell density, as proliferation was reduced. Mechanistically, C3G knock-down impairs EGFR signaling by reducing cell surface EGFR through recycling inhibition, while upregulating the activation of several other receptor tyrosine kinases (RTKs) that might promote invasion. In particular, FGF2, likely acting through FGFR1, promoted invasion of C3G-silenced GBM cells. Moreover, ERKs mediate this invasiveness, both in response to FGF2- and serum-induced chemoattraction. In conclusion, our data show the distinct dependency of GBM tumors on C3G for EGF/EGFR signaling versus other RTKs, suggesting that assessing C3G levels may discriminate GBM patient responders to different RTK inhibition protocols. Hence, patients with a low C3G expression might not respond to EGFR inhibitors. Nature Publishing Group UK 2021-04-06 /pmc/articles/PMC8024353/ /pubmed/33824275 http://dx.doi.org/10.1038/s41419-021-03631-w Text en © The Author(s) 2021 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
Manzano, Sara
Gutierrez-Uzquiza, Alvaro
Bragado, Paloma
Sequera, Celia
Herranz, Óscar
Rodrigo-Faus, María
Jauregui, Patricia
Morgner, Stephanie
Rubio, Ignacio
Guerrero, Carmen
Porras, Almudena
C3G downregulation induces the acquisition of a mesenchymal phenotype that enhances aggressiveness of glioblastoma cells
title C3G downregulation induces the acquisition of a mesenchymal phenotype that enhances aggressiveness of glioblastoma cells
title_full C3G downregulation induces the acquisition of a mesenchymal phenotype that enhances aggressiveness of glioblastoma cells
title_fullStr C3G downregulation induces the acquisition of a mesenchymal phenotype that enhances aggressiveness of glioblastoma cells
title_full_unstemmed C3G downregulation induces the acquisition of a mesenchymal phenotype that enhances aggressiveness of glioblastoma cells
title_short C3G downregulation induces the acquisition of a mesenchymal phenotype that enhances aggressiveness of glioblastoma cells
title_sort c3g downregulation induces the acquisition of a mesenchymal phenotype that enhances aggressiveness of glioblastoma cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8024353/
https://www.ncbi.nlm.nih.gov/pubmed/33824275
http://dx.doi.org/10.1038/s41419-021-03631-w
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