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

Autor: Gabler L; Center for Cancer Research, Medical University of Vienna, Borschkegasse 8A, 1090, Vienna, Austria.; Comprehensive Cancer Center-Central Nervous System Tumor Unit, Medical University of Vienna, Spitalgasse 23, 1090, Vienna, Austria.; Department of Neurosurgery, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria., Jaunecker CN; Center for Cancer Research, Medical University of Vienna, Borschkegasse 8A, 1090, Vienna, Austria.; Comprehensive Cancer Center-Central Nervous System Tumor Unit, Medical University of Vienna, Spitalgasse 23, 1090, Vienna, Austria., Katz S; Center for Cancer Research, Medical University of Vienna, Borschkegasse 8A, 1090, Vienna, Austria., van Schoonhoven S; Center for Cancer Research, Medical University of Vienna, Borschkegasse 8A, 1090, Vienna, Austria., Englinger B; Center for Cancer Research, Medical University of Vienna, Borschkegasse 8A, 1090, Vienna, Austria.; Comprehensive Cancer Center-Central Nervous System Tumor Unit, Medical University of Vienna, Spitalgasse 23, 1090, Vienna, Austria.; Department of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, MA, 02215, USA.; Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA., Pirker C; Center for Cancer Research, Medical University of Vienna, Borschkegasse 8A, 1090, Vienna, Austria.; Comprehensive Cancer Center-Central Nervous System Tumor Unit, Medical University of Vienna, Spitalgasse 23, 1090, Vienna, Austria., Mohr T; Center for Cancer Research, Medical University of Vienna, Borschkegasse 8A, 1090, Vienna, Austria., Vician P; Center for Cancer Research, Medical University of Vienna, Borschkegasse 8A, 1090, Vienna, Austria., Stojanovic M; Center for Cancer Research, Medical University of Vienna, Borschkegasse 8A, 1090, Vienna, Austria., Woitzuck V; Center for Cancer Research, Medical University of Vienna, Borschkegasse 8A, 1090, Vienna, Austria.; Comprehensive Cancer Center-Central Nervous System Tumor Unit, Medical University of Vienna, Spitalgasse 23, 1090, Vienna, Austria., Laemmerer A; Center for Cancer Research, Medical University of Vienna, Borschkegasse 8A, 1090, Vienna, Austria.; Comprehensive Cancer Center-Central Nervous System Tumor Unit, Medical University of Vienna, Spitalgasse 23, 1090, Vienna, Austria.; Department of Pediatrics and Adolescent Medicine and Comprehensive Center for Pediatrics, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria., Kirchhofer D; Center for Cancer Research, Medical University of Vienna, Borschkegasse 8A, 1090, Vienna, Austria.; Comprehensive Cancer Center-Central Nervous System Tumor Unit, Medical University of Vienna, Spitalgasse 23, 1090, Vienna, Austria.; Department of Pediatrics and Adolescent Medicine and Comprehensive Center for Pediatrics, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria., Mayr L; Center for Cancer Research, Medical University of Vienna, Borschkegasse 8A, 1090, Vienna, Austria.; Department of Pediatrics and Adolescent Medicine and Comprehensive Center for Pediatrics, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria., LaFranca M; Center for Cancer Research, Medical University of Vienna, Borschkegasse 8A, 1090, Vienna, Austria.; Comprehensive Cancer Center-Central Nervous System Tumor Unit, Medical University of Vienna, Spitalgasse 23, 1090, Vienna, Austria.; Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, (STEBICEF), University of Palermo, via Archirafi 32, 90123, Palermo, Italy., Erhart F; Department of Neurosurgery, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.; St. Anna Children's Cancer Research Institute, Vienna, Austria., Grissenberger S; St. Anna Children's Cancer Research Institute, Vienna, Austria., Wenninger-Weinzierl A; St. Anna Children's Cancer Research Institute, Vienna, Austria., Sturtzel C; St. Anna Children's Cancer Research Institute, Vienna, Austria., Kiesel B; Department of Neurosurgery, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria., Lang A; Department of Neurosurgery, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria., Marian B; Center for Cancer Research, Medical University of Vienna, Borschkegasse 8A, 1090, Vienna, Austria.; Comprehensive Cancer Center-Central Nervous System Tumor Unit, Medical University of Vienna, Spitalgasse 23, 1090, Vienna, Austria., Grasl-Kraupp B; Center for Cancer Research, Medical University of Vienna, Borschkegasse 8A, 1090, Vienna, Austria.; Comprehensive Cancer Center-Central Nervous System Tumor Unit, Medical University of Vienna, Spitalgasse 23, 1090, Vienna, Austria., Distel M; St. Anna Children's Cancer Research Institute, Vienna, Austria., Schüler J; Charles River Discovery Research Services Germany GmbH, Freiburg, Germany., Gojo J; Center for Cancer Research, Medical University of Vienna, Borschkegasse 8A, 1090, Vienna, Austria.; Department of Pediatrics and Adolescent Medicine and Comprehensive Center for Pediatrics, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria., Grusch M; Center for Cancer Research, Medical University of Vienna, Borschkegasse 8A, 1090, Vienna, Austria., Spiegl-Kreinecker S; Department of Neurosurgery, Kepler University Hospital GmbH, Johannes Kepler University Linz, Wagner-Jauregg-Weg 15, 4020, Linz and Altenberger Strasse 69, 4020, Linz, Austria., Donoghue DJ; Department of Chemistry and Biochemistry, Moores UCSD Cancer Center, University of California San Diego, La Jolla, CA, 92093-0367, USA., Lötsch D; Center for Cancer Research, Medical University of Vienna, Borschkegasse 8A, 1090, Vienna, Austria.; Comprehensive Cancer Center-Central Nervous System Tumor Unit, Medical University of Vienna, Spitalgasse 23, 1090, Vienna, Austria.; Department of Neurosurgery, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria., Berger W; Center for Cancer Research, Medical University of Vienna, Borschkegasse 8A, 1090, Vienna, Austria. walter.berger@meduniwien.ac.at.; Comprehensive Cancer Center-Central Nervous System Tumor Unit, Medical University of Vienna, Spitalgasse 23, 1090, Vienna, Austria. walter.berger@meduniwien.ac.at.
Jazyk: angličtina
Zdroj: Acta neuropathologica communications [Acta Neuropathol Commun] 2022 Apr 28; Vol. 10 (1), pp. 65. Date of Electronic Publication: 2022 Apr 28.
DOI: 10.1186/s40478-022-01363-2
Abstrakt: 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.
(© 2022. The Author(s).)
Databáze: MEDLINE
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