Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2022
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
_version_ 1784696814127022080
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
work_keys_str_mv AT gablerlisa fibroblastgrowthfactorreceptor4promotesglioblastomaprogressionacentralroleofintegrinmediatedcellinvasiveness
AT jauneckercarolanadine fibroblastgrowthfactorreceptor4promotesglioblastomaprogressionacentralroleofintegrinmediatedcellinvasiveness
AT katzsonja fibroblastgrowthfactorreceptor4promotesglioblastomaprogressionacentralroleofintegrinmediatedcellinvasiveness
AT vanschoonhovensushilla fibroblastgrowthfactorreceptor4promotesglioblastomaprogressionacentralroleofintegrinmediatedcellinvasiveness
AT englingerbernhard fibroblastgrowthfactorreceptor4promotesglioblastomaprogressionacentralroleofintegrinmediatedcellinvasiveness
AT pirkerchristine fibroblastgrowthfactorreceptor4promotesglioblastomaprogressionacentralroleofintegrinmediatedcellinvasiveness
AT mohrthomas fibroblastgrowthfactorreceptor4promotesglioblastomaprogressionacentralroleofintegrinmediatedcellinvasiveness
AT vicianpetra fibroblastgrowthfactorreceptor4promotesglioblastomaprogressionacentralroleofintegrinmediatedcellinvasiveness
AT stojanovicmirjana fibroblastgrowthfactorreceptor4promotesglioblastomaprogressionacentralroleofintegrinmediatedcellinvasiveness
AT woitzuckvalentin fibroblastgrowthfactorreceptor4promotesglioblastomaprogressionacentralroleofintegrinmediatedcellinvasiveness
AT laemmereranna fibroblastgrowthfactorreceptor4promotesglioblastomaprogressionacentralroleofintegrinmediatedcellinvasiveness
AT kirchhoferdominik fibroblastgrowthfactorreceptor4promotesglioblastomaprogressionacentralroleofintegrinmediatedcellinvasiveness
AT mayrlisa fibroblastgrowthfactorreceptor4promotesglioblastomaprogressionacentralroleofintegrinmediatedcellinvasiveness
AT lafrancamery fibroblastgrowthfactorreceptor4promotesglioblastomaprogressionacentralroleofintegrinmediatedcellinvasiveness
AT erhartfriedrich fibroblastgrowthfactorreceptor4promotesglioblastomaprogressionacentralroleofintegrinmediatedcellinvasiveness
AT grissenbergersarah fibroblastgrowthfactorreceptor4promotesglioblastomaprogressionacentralroleofintegrinmediatedcellinvasiveness
AT wenningerweinzierlandrea fibroblastgrowthfactorreceptor4promotesglioblastomaprogressionacentralroleofintegrinmediatedcellinvasiveness
AT sturtzelcaterina fibroblastgrowthfactorreceptor4promotesglioblastomaprogressionacentralroleofintegrinmediatedcellinvasiveness
AT kieselbarbara fibroblastgrowthfactorreceptor4promotesglioblastomaprogressionacentralroleofintegrinmediatedcellinvasiveness
AT langalexandra fibroblastgrowthfactorreceptor4promotesglioblastomaprogressionacentralroleofintegrinmediatedcellinvasiveness
AT marianbrigitte fibroblastgrowthfactorreceptor4promotesglioblastomaprogressionacentralroleofintegrinmediatedcellinvasiveness
AT graslkrauppbettina fibroblastgrowthfactorreceptor4promotesglioblastomaprogressionacentralroleofintegrinmediatedcellinvasiveness
AT distelmartin fibroblastgrowthfactorreceptor4promotesglioblastomaprogressionacentralroleofintegrinmediatedcellinvasiveness
AT schulerjulia fibroblastgrowthfactorreceptor4promotesglioblastomaprogressionacentralroleofintegrinmediatedcellinvasiveness
AT gojojohannes fibroblastgrowthfactorreceptor4promotesglioblastomaprogressionacentralroleofintegrinmediatedcellinvasiveness
AT gruschmichael fibroblastgrowthfactorreceptor4promotesglioblastomaprogressionacentralroleofintegrinmediatedcellinvasiveness
AT spieglkreineckersabine fibroblastgrowthfactorreceptor4promotesglioblastomaprogressionacentralroleofintegrinmediatedcellinvasiveness
AT donoghuedanielj fibroblastgrowthfactorreceptor4promotesglioblastomaprogressionacentralroleofintegrinmediatedcellinvasiveness
AT lotschdaniela fibroblastgrowthfactorreceptor4promotesglioblastomaprogressionacentralroleofintegrinmediatedcellinvasiveness
AT bergerwalter fibroblastgrowthfactorreceptor4promotesglioblastomaprogressionacentralroleofintegrinmediatedcellinvasiveness