{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T15:48:46Z","timestamp":1782488926215,"version":"3.54.5"},"reference-count":87,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2022,10,26]],"date-time":"2022-10-26T00:00:00Z","timestamp":1666742400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"University of Bielefeld"},{"name":"Deutsche Forschungsgemeinschaft and the Open Access Publication Fund of Bielefeld University"},{"name":"Bethel Foundation, Bielefeld, Germany"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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-\u03baB, a crucial transcription factor in GBM progression, was expressed in all CD44+\/CD133+\/Nestin+-GSC-populations. Exposure to TNF\u03b1 led to activation of NF-\u03baB-RELA and\/or NF-\u03baB-c-REL, depending on the GBM type. GSCs further expressed the proto-oncogene MYC family, with MYChigh GSCs being predominantly located in the tumor spheres (\u201cGROW\u201d-state) while NF-\u03baB-RELAhigh GSCs were migrating out of the sphere (\u201cGO\u201d-state). We efficiently targeted GSCs by the pharmacologic inhibition of NF-\u03baB 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.<\/jats:p>","DOI":"10.3390\/ijms232112919","type":"journal-article","created":{"date-parts":[[2022,10,26]],"date-time":"2022-10-26T07:17:48Z","timestamp":1666768668000},"page":"12919","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Targeting Key Signaling Pathways in Glioblastoma Stem Cells for the Development of Efficient Chemo- and Immunotherapy"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3520-0558","authenticated-orcid":false,"given":"Laureen P.","family":"Helweg","sequence":"first","affiliation":[{"name":"Department of Cell Biology, University of Bielefeld, Universit\u00e4tsstrasse 25, 33615 Bielefeld, Germany"},{"name":"Forschungsverbund BioMedizin Bielefeld, OWL (FBMB e.V.), Maraweg 21, 33617 Bielefeld, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Storm","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, University of Bielefeld, Universit\u00e4tsstrasse 25, 33615 Bielefeld, Germany"},{"name":"Forschungsverbund BioMedizin Bielefeld, OWL (FBMB e.V.), Maraweg 21, 33617 Bielefeld, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9300-3355","authenticated-orcid":false,"given":"Kaya E.","family":"Witte","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, University of Bielefeld, Universit\u00e4tsstrasse 25, 33615 Bielefeld, Germany"},{"name":"Forschungsverbund BioMedizin Bielefeld, OWL (FBMB e.V.), Maraweg 21, 33617 Bielefeld, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wiebke","family":"Schulten","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, University of Bielefeld, Universit\u00e4tsstrasse 25, 33615 Bielefeld, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lennart","family":"Wrachtrup","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, University of Bielefeld, Universit\u00e4tsstrasse 25, 33615 Bielefeld, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Till","family":"Janotte","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, University of Bielefeld, Universit\u00e4tsstrasse 25, 33615 Bielefeld, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelika","family":"Kitke","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, University of Bielefeld, Universit\u00e4tsstrasse 25, 33615 Bielefeld, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0524-662X","authenticated-orcid":false,"given":"Johannes F. W.","family":"Greiner","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, University of Bielefeld, Universit\u00e4tsstrasse 25, 33615 Bielefeld, Germany"},{"name":"Forschungsverbund BioMedizin Bielefeld, OWL (FBMB e.V.), Maraweg 21, 33617 Bielefeld, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cornelius","family":"Knabbe","sequence":"additional","affiliation":[{"name":"Forschungsverbund BioMedizin Bielefeld, OWL (FBMB e.V.), Maraweg 21, 33617 Bielefeld, Germany"},{"name":"Heart and Diabetes Centre NRW, Institute for Laboratory and Transfusion Medicine, Ruhr-University Bochum, 32545 Bad Oeynhausen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Kaltschmidt","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, University of Bielefeld, Universit\u00e4tsstrasse 25, 33615 Bielefeld, Germany"},{"name":"Forschungsverbund BioMedizin Bielefeld, OWL (FBMB e.V.), Maraweg 21, 33617 Bielefeld, Germany"},{"name":"Molecular Neurobiology, Faculty of Biology, Bielefeld University, Universit\u00e4tsstrasse 25, 33615 Bielefeld, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Simon","sequence":"additional","affiliation":[{"name":"Forschungsverbund BioMedizin Bielefeld, OWL (FBMB e.V.), Maraweg 21, 33617 Bielefeld, Germany"},{"name":"Department of Neurosurgery and Epilepsy Surgery, Protestant Hospital of Bethel Foundation, University Medical School OWL at Bielefeld, Bielefeld University, Campus Bielefeld-Bethel, Burgsteig 13, 33617 Bielefeld, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Kaltschmidt","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, University of Bielefeld, Universit\u00e4tsstrasse 25, 33615 Bielefeld, Germany"},{"name":"Forschungsverbund BioMedizin Bielefeld, OWL (FBMB e.V.), Maraweg 21, 33617 Bielefeld, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"ii1","DOI":"10.1093\/neuonc\/not151","article-title":"CBTRUS statistical report: Primary brain and central nervous system tumors diagnosed in the United States in 2006\u20132010","volume":"15","author":"Ostrom","year":"2013","journal-title":"Neuro Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1902971","DOI":"10.1002\/advs.201902971","article-title":"Advances in the Knowledge of the Molecular Biology of Glioblastoma and Its Impact in Patient Diagnosis, Stratification, and Treatment","volume":"7","author":"Medina","year":"2020","journal-title":"Adv. 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