Targeting Key Signaling Pathways in Glioblastoma Stem Cells for the Development of Efficient Chemo- and Immunotherapy
Glioblastoma multiforme (GBM) is the most aggressive and most common malignant brain tumor with poor patient survival despite therapeutic intervention. On the cellular level, GBM comprises a rare population of glioblastoma stem cells (GSCs), driving therapeutic resistance, invasion, and recurrence....
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-10-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/21/12919 |
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| author | Laureen P. Helweg Jonathan Storm Kaya E. Witte Wiebke Schulten Lennart Wrachtrup Till Janotte Angelika Kitke Johannes F. W. Greiner Cornelius Knabbe Barbara Kaltschmidt Matthias Simon Christian Kaltschmidt |
| author_facet | Laureen P. Helweg Jonathan Storm Kaya E. Witte Wiebke Schulten Lennart Wrachtrup Till Janotte Angelika Kitke Johannes F. W. Greiner Cornelius Knabbe Barbara Kaltschmidt Matthias Simon Christian Kaltschmidt |
| author_sort | Laureen P. Helweg |
| collection | DOAJ |
| description | Glioblastoma multiforme (GBM) is the most aggressive and most common malignant brain tumor with poor patient survival despite therapeutic intervention. On the cellular level, GBM comprises a rare population of glioblastoma stem cells (GSCs), driving therapeutic resistance, invasion, and recurrence. GSCs have thus come into the focus of therapeutic strategies, although their targeting remains challenging. In the present study, we took advantage of three GSCs-populations recently established in our lab to investigate key signaling pathways and subsequent therapeutic strategies targeting GSCs. We observed that NF-κB, a crucial transcription factor in GBM progression, was expressed in all CD44<sup>+</sup>/CD133<sup>+</sup>/Nestin<sup>+</sup>-GSC-populations. Exposure to TNFα led to activation of NF-κB-RELA and/or NF-κB-c-REL, depending on the GBM type. GSCs further expressed the proto-oncogene MYC family, with MYC<sup>high</sup> GSCs being predominantly located in the tumor spheres (“GROW”-state) while NF-κB-RELA<sup>high</sup> GSCs were migrating out of the sphere (“GO”-state). We efficiently targeted GSCs by the pharmacologic inhibition of NF-κB using PTDC/Bortezomib or inhibition of MYC by KJ-Pyr-9, which significantly reduced GSC-viability, even in comparison to the standard chemotherapeutic drug temozolomide. As an additional cell-therapeutic strategy, we showed that NK cells could kill GSCs. Our findings offer new perspectives for developing efficient patient-specific chemo- and immunotherapy against GBM. |
| first_indexed | 2024-03-09T19:01:23Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T19:01:23Z |
| publishDate | 2022-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-3549756f18e346cfb0f397f09068e6c32023-11-24T04:59:32ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-10-0123211291910.3390/ijms232112919Targeting Key Signaling Pathways in Glioblastoma Stem Cells for the Development of Efficient Chemo- and ImmunotherapyLaureen P. Helweg0Jonathan Storm1Kaya E. Witte2Wiebke Schulten3Lennart Wrachtrup4Till Janotte5Angelika Kitke6Johannes F. W. Greiner7Cornelius Knabbe8Barbara Kaltschmidt9Matthias Simon10Christian Kaltschmidt11Department of Cell Biology, University of Bielefeld, Universitätsstrasse 25, 33615 Bielefeld, GermanyDepartment of Cell Biology, University of Bielefeld, Universitätsstrasse 25, 33615 Bielefeld, GermanyDepartment of Cell Biology, University of Bielefeld, Universitätsstrasse 25, 33615 Bielefeld, GermanyDepartment of Cell Biology, University of Bielefeld, Universitätsstrasse 25, 33615 Bielefeld, GermanyDepartment of Cell Biology, University of Bielefeld, Universitätsstrasse 25, 33615 Bielefeld, GermanyDepartment of Cell Biology, University of Bielefeld, Universitätsstrasse 25, 33615 Bielefeld, GermanyDepartment of Cell Biology, University of Bielefeld, Universitätsstrasse 25, 33615 Bielefeld, GermanyDepartment of Cell Biology, University of Bielefeld, Universitätsstrasse 25, 33615 Bielefeld, GermanyForschungsverbund BioMedizin Bielefeld, OWL (FBMB e.V.), Maraweg 21, 33617 Bielefeld, GermanyDepartment of Cell Biology, University of Bielefeld, Universitätsstrasse 25, 33615 Bielefeld, GermanyForschungsverbund BioMedizin Bielefeld, OWL (FBMB e.V.), Maraweg 21, 33617 Bielefeld, GermanyDepartment of Cell Biology, University of Bielefeld, Universitätsstrasse 25, 33615 Bielefeld, GermanyGlioblastoma multiforme (GBM) is the most aggressive and most common malignant brain tumor with poor patient survival despite therapeutic intervention. On the cellular level, GBM comprises a rare population of glioblastoma stem cells (GSCs), driving therapeutic resistance, invasion, and recurrence. GSCs have thus come into the focus of therapeutic strategies, although their targeting remains challenging. In the present study, we took advantage of three GSCs-populations recently established in our lab to investigate key signaling pathways and subsequent therapeutic strategies targeting GSCs. We observed that NF-κB, a crucial transcription factor in GBM progression, was expressed in all CD44<sup>+</sup>/CD133<sup>+</sup>/Nestin<sup>+</sup>-GSC-populations. Exposure to TNFα led to activation of NF-κB-RELA and/or NF-κB-c-REL, depending on the GBM type. GSCs further expressed the proto-oncogene MYC family, with MYC<sup>high</sup> GSCs being predominantly located in the tumor spheres (“GROW”-state) while NF-κB-RELA<sup>high</sup> GSCs were migrating out of the sphere (“GO”-state). We efficiently targeted GSCs by the pharmacologic inhibition of NF-κB using PTDC/Bortezomib or inhibition of MYC by KJ-Pyr-9, which significantly reduced GSC-viability, even in comparison to the standard chemotherapeutic drug temozolomide. As an additional cell-therapeutic strategy, we showed that NK cells could kill GSCs. Our findings offer new perspectives for developing efficient patient-specific chemo- and immunotherapy against GBM.https://www.mdpi.com/1422-0067/23/21/12919glioblastoma multiformecancer stem cellsNF-κBMYCNK-cellschemotherapy |
| spellingShingle | Laureen P. Helweg Jonathan Storm Kaya E. Witte Wiebke Schulten Lennart Wrachtrup Till Janotte Angelika Kitke Johannes F. W. Greiner Cornelius Knabbe Barbara Kaltschmidt Matthias Simon Christian Kaltschmidt Targeting Key Signaling Pathways in Glioblastoma Stem Cells for the Development of Efficient Chemo- and Immunotherapy International Journal of Molecular Sciences glioblastoma multiforme cancer stem cells NF-κB MYC NK-cells chemotherapy |
| title | Targeting Key Signaling Pathways in Glioblastoma Stem Cells for the Development of Efficient Chemo- and Immunotherapy |
| title_full | Targeting Key Signaling Pathways in Glioblastoma Stem Cells for the Development of Efficient Chemo- and Immunotherapy |
| title_fullStr | Targeting Key Signaling Pathways in Glioblastoma Stem Cells for the Development of Efficient Chemo- and Immunotherapy |
| title_full_unstemmed | Targeting Key Signaling Pathways in Glioblastoma Stem Cells for the Development of Efficient Chemo- and Immunotherapy |
| title_short | Targeting Key Signaling Pathways in Glioblastoma Stem Cells for the Development of Efficient Chemo- and Immunotherapy |
| title_sort | targeting key signaling pathways in glioblastoma stem cells for the development of efficient chemo and immunotherapy |
| topic | glioblastoma multiforme cancer stem cells NF-κB MYC NK-cells chemotherapy |
| url | https://www.mdpi.com/1422-0067/23/21/12919 |
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