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J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Epidermal growth factor receptor variant III (EGFRvIII) is a constitutively active EGFR deletion variant found in a subset of glioblastomas (GB). Its association with stem-like tumor populations is well documented, but the outcome of EGFRvIII expression may vary with the developmental and molecular state of the recipient cell. Here, we used human induced pluripotent stem cell (iPSC)-derived, glial fibrillary acidic protein (GFAP)-negative-induced neural stem cells (iNSCs) to explore how this receptor variant affects a defined neural stem\/progenitor background. EGFRvIII was introduced either constitutively by lentiviral transduction or through a doxycycline-responsive Tet-On system. Both experimental approaches were associated with remodeling of the neural stem\/progenitor marker profile, with reduced SRY-box transcription factor 2 (SOX2) expression in the inducible model and significant reductions in both SOX2 and nestin in the constitutive model. Constitutive expression was also associated with increased senescence-associated \u03b2-galactosidase (SA-\u03b2-Gal) activity, while doxycycline induction produced a distinct change in cell-number dynamics at low doxycycline concentration. Thus, in this experimental setting, EGFRvIII was linked to substantial remodeling of the SOX2+\/nestin+ marker profile. These observations do not define a differentiation pathway, prove cellular senescence or malignant transformation, or identify the cell of origin of EGFRvIII-positive GB. Rather, they support the view that the cellular response to EGFRvIII should be considered in relation to the specific neural-glioblastoma precursor context.<\/jats:p>","DOI":"10.3390\/ijms27188118","type":"journal-article","created":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T12:09:51Z","timestamp":1789387791000},"page":"8118","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["EGFRvIII Reduces Neural Stem\/Progenitor Marker Expression in GFAP-Negative iNSCs: Evidence for a Context-Dependent Cellular Response"],"prefix":"10.3390","volume":"27","author":[{"given":"Aneta","family":"W\u0142odarczyk","sequence":"first","affiliation":[{"name":"Department of Tumor Biology, Medical University of Lodz, Zeligowskiego 7\/9, 90-752 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cezary","family":"Tr\u0119da","sequence":"additional","affiliation":[{"name":"Department of Tumor Biology, Medical University of Lodz, Zeligowskiego 7\/9, 90-752 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3588-9140","authenticated-orcid":false,"given":"Dagmara","family":"Grot","sequence":"additional","affiliation":[{"name":"Department of Tumor Biology, Medical University of Lodz, Zeligowskiego 7\/9, 90-752 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ewelina","family":"Stoczy\u0144ska-Fidelus","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, Medical University of Lodz, Zeligowskiego 7\/9, 90-752 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2970-0970","authenticated-orcid":false,"given":"Piotr","family":"Rieske","sequence":"additional","affiliation":[{"name":"Department of Tumor Biology, Medical University of Lodz, Zeligowskiego 7\/9, 90-752 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1354","DOI":"10.1038\/s41423-024-01226-x","article-title":"Immunotherapy for glioblastoma: Current state, challenges, and future perspectives","volume":"21","author":"Liu","year":"2024","journal-title":"Cell. Mol. Immunol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1038\/s41392-025-02299-4","article-title":"Glioblastoma at the crossroads: Current understanding and future therapeutic horizons","volume":"10","author":"Singh","year":"2025","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e70158","DOI":"10.1111\/jnc.70158","article-title":"Status and Prospects of Glioblastoma Multiforme Treatments","volume":"169","author":"Yang","year":"2025","journal-title":"J. Neurochem."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Bonucci, M., Fuggetta, M.P., Anelli, L., Giannarelli, D., Fiorentini, C., and Ravagnan, G. (2025). New Approach for Enhancing Survival in Glioblastoma Patients: A Longitudinal Pilot Study on Integrative Oncology. Cancers, 17.","DOI":"10.20944\/preprints202504.1699.v1"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Loras, A., Gonzalez-Bonet, L.G., Gutierrez-Arroyo, J.L., Martinez-Cadenas, C., and Marques-Torrejon, M.A. (2023). Neural Stem Cells as Potential Glioblastoma Cells of Origin. Life, 13.","DOI":"10.3390\/life13040905"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1186\/s12957-022-02602-5","article-title":"Tracing the origins of glioblastoma by investigating the role of gliogenic and related neurogenic genes\/signaling pathways in GBM development: A systematic review","volume":"20","author":"Shafi","year":"2022","journal-title":"World J. Surg. Oncol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1028","DOI":"10.1038\/s41467-023-36707-6","article-title":"Spatial transcriptomics reveals niche-specific enrichment and vulnerabilities of radial glial stem-like cells in malignant gliomas","volume":"14","author":"Ren","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/j.trecan.2022.10.010","article-title":"Neuronal and tumourigenic boundaries of glioblastoma plasticity","volume":"9","author":"Stringer","year":"2023","journal-title":"Trends Cancer"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Kim, H.J., Park, J.W., and Lee, J.H. (2020). Genetic Architectures and Cell-of-Origin in Glioblastoma. Front. Oncol., 10.","DOI":"10.3389\/fonc.2020.615400"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1238","DOI":"10.1158\/0008-5472.CAN-13-1407","article-title":"Targeting a glioblastoma cancer stem-cell population defined by EGF receptor variant III","volume":"74","author":"Emlet","year":"2014","journal-title":"Cancer Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1038\/s41419-025-07771-1","article-title":"EGFRvIII-positive glioblastoma contributes to immune escape and malignant progression via the c-Fos-MDK-LRP1 axis","volume":"16","author":"Yuan","year":"2025","journal-title":"Cell Death Dis."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Rodriguez, S.M.B., Kamel, A., Ciubotaru, G.V., Onose, G., Sevastre, A.S., Sfredel, V., Danoiu, S., Dricu, A., and Tataranu, L.G. (2023). An Overview of EGFR Mechanisms and Their Implications in Targeted Therapies for Glioblastoma. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241311110"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Wlodarczyk, A., Treda, C., Rutkowska, A., Grot, D., Dobrewa, W., Kierasi\u0144ska, A., W\u0119gierska, M., Wasiak, T., Str\u00f3zik, T., and Rieske, P. (2022). Phenotypical Flexibility of the EGFRvIII-Positive Glioblastoma Cell Line and the Multidirectional Influence of TGF\u03b2 and EGF on These Cells-EGFRvIII Appears as a Weak Oncogene. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232012129"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1092587","DOI":"10.1155\/2019\/1092587","article-title":"EGFRvIII: An Oncogene with Ambiguous Role","volume":"2019","author":"Rutkowska","year":"2019","journal-title":"J. Oncol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2670","DOI":"10.1038\/onc.2012.280","article-title":"EGFRvIII gene rearrangement is an early event in glioblastoma tumorigenesis and expression defines a hierarchy modulated by epigenetic mechanisms","volume":"32","author":"Giacomini","year":"2013","journal-title":"Oncogene"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1038\/s41392-021-00857-0","article-title":"Sox2 induces glioblastoma cell stemness and tumor propagation by repressing TET2 and deregulating 5hmC and 5mC DNA modifications","volume":"7","author":"Johnson","year":"2022","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1016\/j.bbrc.2013.03.021","article-title":"Cell surface Nestin is a biomarker for glioma stem cells","volume":"433","author":"Jin","year":"2013","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"216","DOI":"10.4161\/cbt.26736","article-title":"Differentiation of glioblastoma multiforme stem-like cells leads to downregulation of EGFR and EGFRvIII and decreased tumorigenic and stem-like cell potential","volume":"15","author":"Stockhausen","year":"2014","journal-title":"Cancer Biol. Ther."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1016\/j.cell.2019.06.024","article-title":"An Integrative Model of Cellular States, Plasticity, and Genetics for Glioblastoma","volume":"178","author":"Neftel","year":"2019","journal-title":"Cell"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"4150","DOI":"10.1016\/j.cell.2024.05.059","article-title":"Guidelines for minimal information on cellular senescence experimentation in vivo","volume":"187","author":"Ogrodnik","year":"2024","journal-title":"Cell"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.ymben.2024.09.004","article-title":"A precise and sustainable doxycycline-inducible cell line development platform for reliable mammalian cell engineering with gain-of-function mutations","volume":"86","author":"Shin","year":"2024","journal-title":"Metab. Eng."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"4481","DOI":"10.1038\/s41467-019-12329-9","article-title":"A tunable dual-input system for on-demand dynamic gene expression regulation","volume":"10","author":"Pedone","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"31907","DOI":"10.18632\/oncotarget.8201","article-title":"Cell line with endogenous EGFRvIII expression is a suitable model for research and drug development purposes","volume":"7","author":"Stec","year":"2016","journal-title":"Oncotarget"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Rosiak-Stec, K., Grot, D., and Rieske, P. (2020). Generation of induced neural stem cells with inducible IDH1R132H for analysis of glioma development and drug testing. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0239325"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Janik, K., Treda, C., Wlodarczyk, A., Peciak, J., Rosiak, K., Zieba, J., Grot, D., Rutkowska, A., Pawlowska, R., and Och, W. (2019). A way to understand idiopathic senescence and apoptosis in primary glioblastoma cells\u2014Possible approaches to circumvent these phenomena. 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