Fibroblast growth factor receptor 4 promotes glioblastoma progression: a central role of integrin-mediated cell invasiveness

Abstract 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. Ausführliche Beschreibung

Gespeichert in:

Autor*in:	Lisa Gabler [verfasserIn] Carola Nadine Jaunecker [verfasserIn] Sonja Katz [verfasserIn] Sushilla van Schoonhoven [verfasserIn] Bernhard Englinger [verfasserIn] Christine Pirker [verfasserIn] Thomas Mohr [verfasserIn] Petra Vician [verfasserIn] Mirjana Stojanovic [verfasserIn] Valentin Woitzuck [verfasserIn] Anna Laemmerer [verfasserIn] Dominik Kirchhofer [verfasserIn] Lisa Mayr [verfasserIn] Mery LaFranca [verfasserIn] Friedrich Erhart [verfasserIn] Sarah Grissenberger [verfasserIn] Andrea Wenninger-Weinzierl [verfasserIn] Caterina Sturtzel [verfasserIn] Barbara Kiesel [verfasserIn] Alexandra Lang [verfasserIn] Brigitte Marian [verfasserIn] Bettina Grasl-Kraupp [verfasserIn] Martin Distel [verfasserIn] Julia Schüler [verfasserIn] Johannes Gojo [verfasserIn] Michael Grusch [verfasserIn] Sabine Spiegl-Kreinecker [verfasserIn] Daniel J. Donoghue [verfasserIn] Daniela Lötsch [verfasserIn] Walter Berger [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2022

Schlagwörter:	Glioblastoma FGFR4 Integrins Invasiveness FAK FGF19

Übergeordnetes Werk:	In: Acta Neuropathologica Communications - BMC, 2013, 10(2022), 1, Seite 16
Übergeordnetes Werk:	volume:10 ; year:2022 ; number:1 ; pages:16

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.1186/s40478-022-01363-2

Katalog-ID:	DOAJ03157677X

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allfields	10.1186/s40478-022-01363-2 doi (DE-627)DOAJ03157677X (DE-599)DOAJa09b2bdbe34d4252a9676846e4f372c1 DE-627 ger DE-627 rakwb eng RC346-429 Lisa Gabler verfasserin aut Fibroblast growth factor receptor 4 promotes glioblastoma progression: a central role of integrin-mediated cell invasiveness 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract 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. Glioblastoma FGFR4 Integrins Invasiveness FAK FGF19 Neurology. Diseases of the nervous system Carola Nadine Jaunecker verfasserin aut Sonja Katz verfasserin aut Sushilla van Schoonhoven verfasserin aut Bernhard Englinger verfasserin aut Christine Pirker verfasserin aut Thomas Mohr verfasserin aut Petra Vician verfasserin aut Mirjana Stojanovic verfasserin aut Valentin Woitzuck verfasserin aut Anna Laemmerer verfasserin aut Dominik Kirchhofer verfasserin aut Lisa Mayr verfasserin aut Mery LaFranca verfasserin aut Friedrich Erhart verfasserin aut Sarah Grissenberger verfasserin aut Andrea Wenninger-Weinzierl verfasserin aut Caterina Sturtzel verfasserin aut Barbara Kiesel verfasserin aut Alexandra Lang verfasserin aut Brigitte Marian verfasserin aut Bettina Grasl-Kraupp verfasserin aut Martin Distel verfasserin aut Julia Schüler verfasserin aut Johannes Gojo verfasserin aut Michael Grusch verfasserin aut Sabine Spiegl-Kreinecker verfasserin aut Daniel J. Donoghue verfasserin aut Daniela Lötsch verfasserin aut Walter Berger verfasserin aut In Acta Neuropathologica Communications BMC, 2013 10(2022), 1, Seite 16 (DE-627)746066465 (DE-600)2715589-4 20515960 nnns volume:10 year:2022 number:1 pages:16 https://doi.org/10.1186/s40478-022-01363-2 kostenfrei https://doaj.org/article/a09b2bdbe34d4252a9676846e4f372c1 kostenfrei https://doi.org/10.1186/s40478-022-01363-2 kostenfrei https://doaj.org/toc/2051-5960 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 10 2022 1 16
spelling	10.1186/s40478-022-01363-2 doi (DE-627)DOAJ03157677X (DE-599)DOAJa09b2bdbe34d4252a9676846e4f372c1 DE-627 ger DE-627 rakwb eng RC346-429 Lisa Gabler verfasserin aut Fibroblast growth factor receptor 4 promotes glioblastoma progression: a central role of integrin-mediated cell invasiveness 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract 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. Glioblastoma FGFR4 Integrins Invasiveness FAK FGF19 Neurology. Diseases of the nervous system Carola Nadine Jaunecker verfasserin aut Sonja Katz verfasserin aut Sushilla van Schoonhoven verfasserin aut Bernhard Englinger verfasserin aut Christine Pirker verfasserin aut Thomas Mohr verfasserin aut Petra Vician verfasserin aut Mirjana Stojanovic verfasserin aut Valentin Woitzuck verfasserin aut Anna Laemmerer verfasserin aut Dominik Kirchhofer verfasserin aut Lisa Mayr verfasserin aut Mery LaFranca verfasserin aut Friedrich Erhart verfasserin aut Sarah Grissenberger verfasserin aut Andrea Wenninger-Weinzierl verfasserin aut Caterina Sturtzel verfasserin aut Barbara Kiesel verfasserin aut Alexandra Lang verfasserin aut Brigitte Marian verfasserin aut Bettina Grasl-Kraupp verfasserin aut Martin Distel verfasserin aut Julia Schüler verfasserin aut Johannes Gojo verfasserin aut Michael Grusch verfasserin aut Sabine Spiegl-Kreinecker verfasserin aut Daniel J. Donoghue verfasserin aut Daniela Lötsch verfasserin aut Walter Berger verfasserin aut In Acta Neuropathologica Communications BMC, 2013 10(2022), 1, Seite 16 (DE-627)746066465 (DE-600)2715589-4 20515960 nnns volume:10 year:2022 number:1 pages:16 https://doi.org/10.1186/s40478-022-01363-2 kostenfrei https://doaj.org/article/a09b2bdbe34d4252a9676846e4f372c1 kostenfrei https://doi.org/10.1186/s40478-022-01363-2 kostenfrei https://doaj.org/toc/2051-5960 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 10 2022 1 16
allfields_unstemmed	10.1186/s40478-022-01363-2 doi (DE-627)DOAJ03157677X (DE-599)DOAJa09b2bdbe34d4252a9676846e4f372c1 DE-627 ger DE-627 rakwb eng RC346-429 Lisa Gabler verfasserin aut Fibroblast growth factor receptor 4 promotes glioblastoma progression: a central role of integrin-mediated cell invasiveness 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract 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. Glioblastoma FGFR4 Integrins Invasiveness FAK FGF19 Neurology. Diseases of the nervous system Carola Nadine Jaunecker verfasserin aut Sonja Katz verfasserin aut Sushilla van Schoonhoven verfasserin aut Bernhard Englinger verfasserin aut Christine Pirker verfasserin aut Thomas Mohr verfasserin aut Petra Vician verfasserin aut Mirjana Stojanovic verfasserin aut Valentin Woitzuck verfasserin aut Anna Laemmerer verfasserin aut Dominik Kirchhofer verfasserin aut Lisa Mayr verfasserin aut Mery LaFranca verfasserin aut Friedrich Erhart verfasserin aut Sarah Grissenberger verfasserin aut Andrea Wenninger-Weinzierl verfasserin aut Caterina Sturtzel verfasserin aut Barbara Kiesel verfasserin aut Alexandra Lang verfasserin aut Brigitte Marian verfasserin aut Bettina Grasl-Kraupp verfasserin aut Martin Distel verfasserin aut Julia Schüler verfasserin aut Johannes Gojo verfasserin aut Michael Grusch verfasserin aut Sabine Spiegl-Kreinecker verfasserin aut Daniel J. Donoghue verfasserin aut Daniela Lötsch verfasserin aut Walter Berger verfasserin aut In Acta Neuropathologica Communications BMC, 2013 10(2022), 1, Seite 16 (DE-627)746066465 (DE-600)2715589-4 20515960 nnns volume:10 year:2022 number:1 pages:16 https://doi.org/10.1186/s40478-022-01363-2 kostenfrei https://doaj.org/article/a09b2bdbe34d4252a9676846e4f372c1 kostenfrei https://doi.org/10.1186/s40478-022-01363-2 kostenfrei https://doaj.org/toc/2051-5960 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 10 2022 1 16
allfieldsGer	10.1186/s40478-022-01363-2 doi (DE-627)DOAJ03157677X (DE-599)DOAJa09b2bdbe34d4252a9676846e4f372c1 DE-627 ger DE-627 rakwb eng RC346-429 Lisa Gabler verfasserin aut Fibroblast growth factor receptor 4 promotes glioblastoma progression: a central role of integrin-mediated cell invasiveness 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract 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. Glioblastoma FGFR4 Integrins Invasiveness FAK FGF19 Neurology. Diseases of the nervous system Carola Nadine Jaunecker verfasserin aut Sonja Katz verfasserin aut Sushilla van Schoonhoven verfasserin aut Bernhard Englinger verfasserin aut Christine Pirker verfasserin aut Thomas Mohr verfasserin aut Petra Vician verfasserin aut Mirjana Stojanovic verfasserin aut Valentin Woitzuck verfasserin aut Anna Laemmerer verfasserin aut Dominik Kirchhofer verfasserin aut Lisa Mayr verfasserin aut Mery LaFranca verfasserin aut Friedrich Erhart verfasserin aut Sarah Grissenberger verfasserin aut Andrea Wenninger-Weinzierl verfasserin aut Caterina Sturtzel verfasserin aut Barbara Kiesel verfasserin aut Alexandra Lang verfasserin aut Brigitte Marian verfasserin aut Bettina Grasl-Kraupp verfasserin aut Martin Distel verfasserin aut Julia Schüler verfasserin aut Johannes Gojo verfasserin aut Michael Grusch verfasserin aut Sabine Spiegl-Kreinecker verfasserin aut Daniel J. Donoghue verfasserin aut Daniela Lötsch verfasserin aut Walter Berger verfasserin aut In Acta Neuropathologica Communications BMC, 2013 10(2022), 1, Seite 16 (DE-627)746066465 (DE-600)2715589-4 20515960 nnns volume:10 year:2022 number:1 pages:16 https://doi.org/10.1186/s40478-022-01363-2 kostenfrei https://doaj.org/article/a09b2bdbe34d4252a9676846e4f372c1 kostenfrei https://doi.org/10.1186/s40478-022-01363-2 kostenfrei https://doaj.org/toc/2051-5960 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 10 2022 1 16
allfieldsSound	10.1186/s40478-022-01363-2 doi (DE-627)DOAJ03157677X (DE-599)DOAJa09b2bdbe34d4252a9676846e4f372c1 DE-627 ger DE-627 rakwb eng RC346-429 Lisa Gabler verfasserin aut Fibroblast growth factor receptor 4 promotes glioblastoma progression: a central role of integrin-mediated cell invasiveness 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract 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. Glioblastoma FGFR4 Integrins Invasiveness FAK FGF19 Neurology. Diseases of the nervous system Carola Nadine Jaunecker verfasserin aut Sonja Katz verfasserin aut Sushilla van Schoonhoven verfasserin aut Bernhard Englinger verfasserin aut Christine Pirker verfasserin aut Thomas Mohr verfasserin aut Petra Vician verfasserin aut Mirjana Stojanovic verfasserin aut Valentin Woitzuck verfasserin aut Anna Laemmerer verfasserin aut Dominik Kirchhofer verfasserin aut Lisa Mayr verfasserin aut Mery LaFranca verfasserin aut Friedrich Erhart verfasserin aut Sarah Grissenberger verfasserin aut Andrea Wenninger-Weinzierl verfasserin aut Caterina Sturtzel verfasserin aut Barbara Kiesel verfasserin aut Alexandra Lang verfasserin aut Brigitte Marian verfasserin aut Bettina Grasl-Kraupp verfasserin aut Martin Distel verfasserin aut Julia Schüler verfasserin aut Johannes Gojo verfasserin aut Michael Grusch verfasserin aut Sabine Spiegl-Kreinecker verfasserin aut Daniel J. Donoghue verfasserin aut Daniela Lötsch verfasserin aut Walter Berger verfasserin aut In Acta Neuropathologica Communications BMC, 2013 10(2022), 1, Seite 16 (DE-627)746066465 (DE-600)2715589-4 20515960 nnns volume:10 year:2022 number:1 pages:16 https://doi.org/10.1186/s40478-022-01363-2 kostenfrei https://doaj.org/article/a09b2bdbe34d4252a9676846e4f372c1 kostenfrei https://doi.org/10.1186/s40478-022-01363-2 kostenfrei https://doaj.org/toc/2051-5960 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 10 2022 1 16
language	English
source	In Acta Neuropathologica Communications 10(2022), 1, Seite 16 volume:10 year:2022 number:1 pages:16
sourceStr	In Acta Neuropathologica Communications 10(2022), 1, Seite 16 volume:10 year:2022 number:1 pages:16
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	Glioblastoma FGFR4 Integrins Invasiveness FAK FGF19 Neurology. Diseases of the nervous system
isfreeaccess_bool	true
container_title	Acta Neuropathologica Communications
authorswithroles_txt_mv	Lisa Gabler @@aut@@ Carola Nadine Jaunecker @@aut@@ Sonja Katz @@aut@@ Sushilla van Schoonhoven @@aut@@ Bernhard Englinger @@aut@@ Christine Pirker @@aut@@ Thomas Mohr @@aut@@ Petra Vician @@aut@@ Mirjana Stojanovic @@aut@@ Valentin Woitzuck @@aut@@ Anna Laemmerer @@aut@@ Dominik Kirchhofer @@aut@@ Lisa Mayr @@aut@@ Mery LaFranca @@aut@@ Friedrich Erhart @@aut@@ Sarah Grissenberger @@aut@@ Andrea Wenninger-Weinzierl @@aut@@ Caterina Sturtzel @@aut@@ Barbara Kiesel @@aut@@ Alexandra Lang @@aut@@ Brigitte Marian @@aut@@ Bettina Grasl-Kraupp @@aut@@ Martin Distel @@aut@@ Julia Schüler @@aut@@ Johannes Gojo @@aut@@ Michael Grusch @@aut@@ Sabine Spiegl-Kreinecker @@aut@@ Daniel J. Donoghue @@aut@@ Daniela Lötsch @@aut@@ Walter Berger @@aut@@
publishDateDaySort_date	2022-01-01T00:00:00Z
hierarchy_top_id	746066465
id	DOAJ03157677X
language_de	englisch
fullrecord	<?xml version="1.0" encoding="UTF-8"?><collection xmlns="http://www.loc.gov/MARC21/slim"><record><leader>01000caa a22002652 4500</leader><controlfield tag="001">DOAJ03157677X</controlfield><controlfield tag="003">DE-627</controlfield><controlfield tag="005">20230307161741.0</controlfield><controlfield tag="007">cr uuu---uuuuu</controlfield><controlfield tag="008">230226s2022 xx \|\|\|\|\|o 00\| \|\|eng c</controlfield><datafield tag="024" ind1="7" ind2=" "><subfield code="a">10.1186/s40478-022-01363-2</subfield><subfield code="2">doi</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-627)DOAJ03157677X</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-599)DOAJa09b2bdbe34d4252a9676846e4f372c1</subfield></datafield><datafield tag="040" ind1=" " ind2=" "><subfield code="a">DE-627</subfield><subfield code="b">ger</subfield><subfield code="c">DE-627</subfield><subfield code="e">rakwb</subfield></datafield><datafield tag="041" ind1=" " ind2=" "><subfield code="a">eng</subfield></datafield><datafield tag="050" ind1=" " ind2="0"><subfield code="a">RC346-429</subfield></datafield><datafield tag="100" ind1="0" ind2=" "><subfield code="a">Lisa Gabler</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="0"><subfield code="a">Fibroblast growth factor receptor 4 promotes glioblastoma progression: a central role of integrin-mediated cell invasiveness</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">2022</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">Text</subfield><subfield code="b">txt</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">Computermedien</subfield><subfield code="b">c</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">Online-Ressource</subfield><subfield code="b">cr</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Abstract 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. 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callnumber-first	R - Medicine
author	Lisa Gabler
spellingShingle	Lisa Gabler misc RC346-429 misc Glioblastoma misc FGFR4 misc Integrins misc Invasiveness misc FAK misc FGF19 misc Neurology. Diseases of the nervous system Fibroblast growth factor receptor 4 promotes glioblastoma progression: a central role of integrin-mediated cell invasiveness
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topic_title	RC346-429 Fibroblast growth factor receptor 4 promotes glioblastoma progression: a central role of integrin-mediated cell invasiveness Glioblastoma FGFR4 Integrins Invasiveness FAK FGF19
topic	misc RC346-429 misc Glioblastoma misc FGFR4 misc Integrins misc Invasiveness misc FAK misc FGF19 misc Neurology. Diseases of the nervous system
topic_unstemmed	misc RC346-429 misc Glioblastoma misc FGFR4 misc Integrins misc Invasiveness misc FAK misc FGF19 misc Neurology. Diseases of the nervous system
topic_browse	misc RC346-429 misc Glioblastoma misc FGFR4 misc Integrins misc Invasiveness misc FAK misc FGF19 misc Neurology. Diseases of the nervous system
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title	Fibroblast growth factor receptor 4 promotes glioblastoma progression: a central role of integrin-mediated cell invasiveness
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title_full	Fibroblast growth factor receptor 4 promotes glioblastoma progression: a central role of integrin-mediated cell invasiveness
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author_browse	Lisa Gabler Carola Nadine Jaunecker Sonja Katz Sushilla van Schoonhoven Bernhard Englinger Christine Pirker Thomas Mohr Petra Vician Mirjana Stojanovic Valentin Woitzuck Anna Laemmerer Dominik Kirchhofer Lisa Mayr Mery LaFranca Friedrich Erhart Sarah Grissenberger Andrea Wenninger-Weinzierl Caterina Sturtzel Barbara Kiesel Alexandra Lang Brigitte Marian Bettina Grasl-Kraupp Martin Distel Julia Schüler Johannes Gojo Michael Grusch Sabine Spiegl-Kreinecker Daniel J. Donoghue Daniela Lötsch Walter Berger
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title_sort	fibroblast growth factor receptor 4 promotes glioblastoma progression: a central role of integrin-mediated cell invasiveness
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title_auth	Fibroblast growth factor receptor 4 promotes glioblastoma progression: a central role of integrin-mediated cell invasiveness
abstract	Abstract 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.
abstractGer	Abstract 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.
abstract_unstemmed	Abstract 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.
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title_short	Fibroblast growth factor receptor 4 promotes glioblastoma progression: a central role of integrin-mediated cell invasiveness
url	https://doi.org/10.1186/s40478-022-01363-2 https://doaj.org/article/a09b2bdbe34d4252a9676846e4f372c1 https://doaj.org/toc/2051-5960
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fullrecord_marcxml	<?xml version="1.0" encoding="UTF-8"?><collection xmlns="http://www.loc.gov/MARC21/slim"><record><leader>01000caa a22002652 4500</leader><controlfield tag="001">DOAJ03157677X</controlfield><controlfield tag="003">DE-627</controlfield><controlfield tag="005">20230307161741.0</controlfield><controlfield tag="007">cr uuu---uuuuu</controlfield><controlfield tag="008">230226s2022 xx \|\|\|\|\|o 00\| \|\|eng c</controlfield><datafield tag="024" ind1="7" ind2=" "><subfield code="a">10.1186/s40478-022-01363-2</subfield><subfield code="2">doi</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-627)DOAJ03157677X</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-599)DOAJa09b2bdbe34d4252a9676846e4f372c1</subfield></datafield><datafield tag="040" ind1=" " ind2=" "><subfield code="a">DE-627</subfield><subfield code="b">ger</subfield><subfield code="c">DE-627</subfield><subfield code="e">rakwb</subfield></datafield><datafield tag="041" ind1=" " ind2=" "><subfield code="a">eng</subfield></datafield><datafield tag="050" ind1=" " ind2="0"><subfield code="a">RC346-429</subfield></datafield><datafield tag="100" ind1="0" ind2=" "><subfield code="a">Lisa Gabler</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="0"><subfield code="a">Fibroblast growth factor receptor 4 promotes glioblastoma progression: a central role of integrin-mediated cell invasiveness</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">2022</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">Text</subfield><subfield code="b">txt</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">Computermedien</subfield><subfield code="b">c</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">Online-Ressource</subfield><subfield code="b">cr</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Abstract 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. 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Fibroblast growth factor receptor 4 promotes glioblastoma progression: a central role of integrin-mediated cell invasiveness

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