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Fibroblast growth factor receptor 4 promotes glioblastoma progression: a central role of integrin-mediated cell invasiveness
Glioblastoma (GBM) is characterized by a particularly invasive phenotype, supported by oncogenic signals from the fibroblast growth factor (FGF)/ FGF receptor (FGFR) network. However, a possible role of FGFR4 remained elusive so far. Several transcriptomic glioma datasets were analyzed. An extended...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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BioMed Central
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9052585/ https://www.ncbi.nlm.nih.gov/pubmed/35484633 http://dx.doi.org/10.1186/s40478-022-01363-2 |
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author | Gabler, Lisa Jaunecker, Carola Nadine Katz, Sonja van Schoonhoven, Sushilla Englinger, Bernhard Pirker, Christine Mohr, Thomas Vician, Petra Stojanovic, Mirjana Woitzuck, Valentin Laemmerer, Anna Kirchhofer, Dominik Mayr, Lisa LaFranca, Mery Erhart, Friedrich Grissenberger, Sarah Wenninger-Weinzierl, Andrea Sturtzel, Caterina Kiesel, Barbara Lang, Alexandra Marian, Brigitte Grasl-Kraupp, Bettina Distel, Martin Schüler, Julia Gojo, Johannes Grusch, Michael Spiegl-Kreinecker, Sabine Donoghue, Daniel J. Lötsch, Daniela Berger, Walter |
author_facet | Gabler, Lisa Jaunecker, Carola Nadine Katz, Sonja van Schoonhoven, Sushilla Englinger, Bernhard Pirker, Christine Mohr, Thomas Vician, Petra Stojanovic, Mirjana Woitzuck, Valentin Laemmerer, Anna Kirchhofer, Dominik Mayr, Lisa LaFranca, Mery Erhart, Friedrich Grissenberger, Sarah Wenninger-Weinzierl, Andrea Sturtzel, Caterina Kiesel, Barbara Lang, Alexandra Marian, Brigitte Grasl-Kraupp, Bettina Distel, Martin Schüler, Julia Gojo, Johannes Grusch, Michael Spiegl-Kreinecker, Sabine Donoghue, Daniel J. Lötsch, Daniela Berger, Walter |
author_sort | Gabler, Lisa |
collection | PubMed |
description | Glioblastoma (GBM) is characterized by a particularly invasive phenotype, supported by oncogenic signals from the fibroblast growth factor (FGF)/ FGF receptor (FGFR) network. However, a possible role of FGFR4 remained elusive so far. Several transcriptomic glioma datasets were analyzed. An extended panel of primary surgical specimen-derived and immortalized GBM (stem)cell models and original tumor tissues were screened for FGFR4 expression. GBM models engineered for wild-type and dominant-negative FGFR4 overexpression were investigated regarding aggressiveness and xenograft formation. Gene set enrichment analyses of FGFR4-modulated GBM models were compared to patient-derived datasets. Despite widely absent in adult brain, FGFR4 mRNA was distinctly expressed in embryonic neural stem cells and significantly upregulated in glioblastoma. Pronounced FGFR4 overexpression defined a distinct GBM patient subgroup with dismal prognosis. Expression levels of FGFR4 and its specific ligands FGF19/FGF23 correlated both in vitro and in vivo and were progressively upregulated in the vast majority of recurrent tumors. Based on overexpression/blockade experiments in respective GBM models, a central pro-oncogenic function of FGFR4 concerning viability, adhesion, migration, and clonogenicity was identified. Expression of dominant-negative FGFR4 resulted in diminished (subcutaneous) or blocked (orthotopic) GBM xenograft formation in the mouse and reduced invasiveness in zebrafish xenotransplantation models. In vitro and in vivo data consistently revealed distinct FGFR4 and integrin/extracellular matrix interactions. Accordingly, FGFR4 blockade profoundly sensitized FGFR4-overexpressing GBM models towards integrin/focal adhesion kinase inhibitors. Collectively, FGFR4 overexpression contributes to the malignant phenotype of a highly aggressive GBM subgroup and is associated with integrin-related therapeutic vulnerabilities. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40478-022-01363-2. |
format | Online Article Text |
id | pubmed-9052585 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-90525852022-04-30 Fibroblast growth factor receptor 4 promotes glioblastoma progression: a central role of integrin-mediated cell invasiveness Gabler, Lisa Jaunecker, Carola Nadine Katz, Sonja van Schoonhoven, Sushilla Englinger, Bernhard Pirker, Christine Mohr, Thomas Vician, Petra Stojanovic, Mirjana Woitzuck, Valentin Laemmerer, Anna Kirchhofer, Dominik Mayr, Lisa LaFranca, Mery Erhart, Friedrich Grissenberger, Sarah Wenninger-Weinzierl, Andrea Sturtzel, Caterina Kiesel, Barbara Lang, Alexandra Marian, Brigitte Grasl-Kraupp, Bettina Distel, Martin Schüler, Julia Gojo, Johannes Grusch, Michael Spiegl-Kreinecker, Sabine Donoghue, Daniel J. Lötsch, Daniela Berger, Walter Acta Neuropathol Commun Research Glioblastoma (GBM) is characterized by a particularly invasive phenotype, supported by oncogenic signals from the fibroblast growth factor (FGF)/ FGF receptor (FGFR) network. However, a possible role of FGFR4 remained elusive so far. Several transcriptomic glioma datasets were analyzed. An extended panel of primary surgical specimen-derived and immortalized GBM (stem)cell models and original tumor tissues were screened for FGFR4 expression. GBM models engineered for wild-type and dominant-negative FGFR4 overexpression were investigated regarding aggressiveness and xenograft formation. Gene set enrichment analyses of FGFR4-modulated GBM models were compared to patient-derived datasets. Despite widely absent in adult brain, FGFR4 mRNA was distinctly expressed in embryonic neural stem cells and significantly upregulated in glioblastoma. Pronounced FGFR4 overexpression defined a distinct GBM patient subgroup with dismal prognosis. Expression levels of FGFR4 and its specific ligands FGF19/FGF23 correlated both in vitro and in vivo and were progressively upregulated in the vast majority of recurrent tumors. Based on overexpression/blockade experiments in respective GBM models, a central pro-oncogenic function of FGFR4 concerning viability, adhesion, migration, and clonogenicity was identified. Expression of dominant-negative FGFR4 resulted in diminished (subcutaneous) or blocked (orthotopic) GBM xenograft formation in the mouse and reduced invasiveness in zebrafish xenotransplantation models. In vitro and in vivo data consistently revealed distinct FGFR4 and integrin/extracellular matrix interactions. Accordingly, FGFR4 blockade profoundly sensitized FGFR4-overexpressing GBM models towards integrin/focal adhesion kinase inhibitors. Collectively, FGFR4 overexpression contributes to the malignant phenotype of a highly aggressive GBM subgroup and is associated with integrin-related therapeutic vulnerabilities. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40478-022-01363-2. BioMed Central 2022-04-28 /pmc/articles/PMC9052585/ /pubmed/35484633 http://dx.doi.org/10.1186/s40478-022-01363-2 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Gabler, Lisa Jaunecker, Carola Nadine Katz, Sonja van Schoonhoven, Sushilla Englinger, Bernhard Pirker, Christine Mohr, Thomas Vician, Petra Stojanovic, Mirjana Woitzuck, Valentin Laemmerer, Anna Kirchhofer, Dominik Mayr, Lisa LaFranca, Mery Erhart, Friedrich Grissenberger, Sarah Wenninger-Weinzierl, Andrea Sturtzel, Caterina Kiesel, Barbara Lang, Alexandra Marian, Brigitte Grasl-Kraupp, Bettina Distel, Martin Schüler, Julia Gojo, Johannes Grusch, Michael Spiegl-Kreinecker, Sabine Donoghue, Daniel J. Lötsch, Daniela Berger, Walter Fibroblast growth factor receptor 4 promotes glioblastoma progression: a central role of integrin-mediated cell invasiveness |
title | Fibroblast growth factor receptor 4 promotes glioblastoma progression: a central role of integrin-mediated cell invasiveness |
title_full | Fibroblast growth factor receptor 4 promotes glioblastoma progression: a central role of integrin-mediated cell invasiveness |
title_fullStr | Fibroblast growth factor receptor 4 promotes glioblastoma progression: a central role of integrin-mediated cell invasiveness |
title_full_unstemmed | Fibroblast growth factor receptor 4 promotes glioblastoma progression: a central role of integrin-mediated cell invasiveness |
title_short | Fibroblast growth factor receptor 4 promotes glioblastoma progression: a central role of integrin-mediated cell invasiveness |
title_sort | fibroblast growth factor receptor 4 promotes glioblastoma progression: a central role of integrin-mediated cell invasiveness |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9052585/ https://www.ncbi.nlm.nih.gov/pubmed/35484633 http://dx.doi.org/10.1186/s40478-022-01363-2 |
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