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| Verfasst von: | Alhalabi, Obada [VerfasserIn]  |
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| | Göttmann, Mona [VerfasserIn] |
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| | Gold, Maxwell P. [VerfasserIn] |
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| | Schlue, Silja [VerfasserIn] |
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| | Hielscher, Thomas [VerfasserIn] |
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| | Iskar, Murat [VerfasserIn] |
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| | Keßler, Tobias [VerfasserIn] |
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| | Hai, Ling [VerfasserIn] |
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| | Lokumcu, Tolga [VerfasserIn] |
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| | Cousins, Clara C. [VerfasserIn] |
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| | Herold-Mende, Christel [VerfasserIn] |
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| | Heßling, Bernd [VerfasserIn] |
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| | Horschitz, Sandra [VerfasserIn] |
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| | Jabali, Ammar [VerfasserIn] |
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| | Koch, Philipp [VerfasserIn] |
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| | Baumgartner, Ulrich [VerfasserIn] |
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| | Day, Bryan W. [VerfasserIn] |
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| | Wick, Wolfgang [VerfasserIn] |
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| | Sahm, Felix [VerfasserIn] |
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| | Krieg, Sandro [VerfasserIn] |
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| | Fraenkel, Ernest [VerfasserIn] |
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| | Phillips, Emma [VerfasserIn] |
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| | Goidts, Violaine [VerfasserIn] |
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| Titel: | Integration of transcriptomics, proteomics and loss-of-function screening reveals WEE1 as a target for combination with dasatinib against proneural glioblastoma |
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| Verf.angabe: | Obada T. Alhalabi, Mona Göttmann, Maxwell P. Gold, Silja Schlue, Thomas Hielscher, Murat Iskar, Tobias Kessler, Ling Hai, Tolga Lokumcu, Clara C. Cousins, Christel Herold-Mende, Bernd Heßling, Sandra Horschitz, Ammar Jabali, Philipp Koch, Ulrich Baumgartner, Bryan W. Day, Wolfgang Wick, Felix Sahm, Sandro M. Krieg, Ernest Fraenkel, Emma Phillips, Violaine Goidts |
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| E-Jahr: | 2024 |
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| Jahr: | 28 November 2024 |
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| Umfang: | 14 S. |
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| Illustrationen: | Illustrationen |
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| Fussnoten: | Online verfügbar: 25. September 2024, Artikelversion: 3. Oktober 2024 ; Gesehen am 14.05.2025 |
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| Titel Quelle: | Enthalten in: Cancer letters |
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| Ort Quelle: | Amsterdam [u.a.] : Elsevier Science, 1975 |
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| Jahr Quelle: | 2024 |
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| Band/Heft Quelle: | 605(2024), Artikel-ID 217265, Seite 1-14 |
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| ISSN Quelle: | 1872-7980 |
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| Abstract: | Glioblastoma is characterized by a pronounced resistance to therapy with dismal prognosis. Transcriptomics classify glioblastoma into proneural (PN), mesenchymal (MES) and classical (CL) subtypes that show differential resistance to targeted therapies. The aim of this study was to provide a viable approach for identifying combination therapies in glioblastoma subtypes. Proteomics and phosphoproteomics were performed on dasatinib inhibited glioblastoma stem cells (GSCs) and complemented by an shRNA loss-of-function screen to identify genes whose knockdown sensitizes GSCs to dasatinib. Proteomics and screen data were computationally integrated with transcriptomic data using the SamNet 2.0 algorithm for network flow learning to reveal potential combination therapies in PN GSCs. In vitro viability assays and tumor spheroid models were used to verify the synergy of identified therapy. Further in vitro and TCGA RNA-Seq data analyses were utilized to provide a mechanistic explanation of these effects. Integration of data revealed the cell cycle protein WEE1 as a potential combination therapy target for PN GSCs. Validation experiments showed a robust synergistic effect through combination of dasatinib and the WEE1 inhibitor, MK-1775, in PN GSCs. Combined inhibition using dasatinib and MK-1775 propagated DNA damage in PN GCSs, with GCSs showing a differential subtype-driven pattern of expression of cell cycle genes in TCGA RNA-Seq data. The integration of proteomics, loss-of-function screens and transcriptomics confirmed WEE1 as a target for combination with dasatinib against PN GSCs. Utilizing this integrative approach could be of interest for studying resistance mechanisms and revealing combination therapy targets in further tumor entities. |
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| DOI: | doi:10.1016/j.canlet.2024.217265 |
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| URL: | Bitte beachten Sie: Dies ist ein Bibliographieeintrag. Ein Volltextzugriff für Mitglieder der Universität besteht hier nur, falls für die entsprechende Zeitschrift/den entsprechenden Sammelband ein Abonnement besteht oder es sich um einen OpenAccess-Titel handelt.
kostenfrei: Volltext: https://doi.org/10.1016/j.canlet.2024.217265 |
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| | kostenfrei: Volltext: https://www.sciencedirect.com/science/article/pii/S0304383524006608 |
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| | DOI: https://doi.org/10.1016/j.canlet.2024.217265 |
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| Datenträger: | Online-Ressource |
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| Sprache: | eng |
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| Sach-SW: | Computational integration |
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| | Dasatinib |
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| | Loss-of-function shRNA screen |
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| | Phosphoproteomics |
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| | WEE1 |
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| K10plus-PPN: | 1925641511 |
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| Verknüpfungen: | → Zeitschrift |
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Integration of transcriptomics, proteomics and loss-of-function screening reveals WEE1 as a target for combination with dasatinib against proneural glioblastoma / Alhalabi, Obada [VerfasserIn]; 28 November 2024 (Online-Ressource)
