Impact of developmental state, p53 status, and interferon signaling on glioblastoma cell response to radiation and temozolomide treatment
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Le résumé fourni par la source
Glioblastoma (GBM) tumors exhibit extensive genomic, epigenomic, and transcriptional diversity, with significant intratumoral heterogeneity, complicating standard treatment approaches involving radiation (RT) and the DNA-alkylating agent temozolomide (TMZ). In this study, we employed an integrative multi-omics approach, including targeted proteomics, transcriptomics, genomics, and DNA methylation profiling, to investigate the response of a representative panel of GBM patient-derived cancer stem cells (CSCs) to astrocytic differentiation and RT and TMZ treatments. Differentiated CSC progenies retained the expression of key stemness genes and survival pathways, while activating the BMP-Smad signaling pathway and upregulating extracellular matrix components. This was associated with increased resistance to TMZ, though not to RT, across all models. We identified TP53 status as a critical determinant of transcriptional response to both RT and TMZ, which was also modulated by the differentiation state and treatment modality in wildtype (wt) p53 GBM cells. Both mutant and wt p53 models exhibited significant activation of the DNA-damage associated interferon (IFN) response in CSCs and differentiated cells, implicating this pathway in the GBM response to therapy. We observed that activation of NF-κB was positively correlated with the levels of O-6-methylguanine-DNA methyltransferase (MGMT) protein, a direct DNA repair enzyme leading to TMZ resistance, regardless of MGMT promoter methylation status, further supporting the clinical potential for inhibition of NF-kB signaling in GBM treatment. Our integrative analysis of the impact of GBM cell developmental states, in the context of genomic and molecular diversity of patient-derived models, provides valuable insights for pre-clinical studies aimed at optimizing treatment strategies.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Impact of developmental state, p53 status, and interferon signaling on glioblastoma cell response to radiation and temozolomide treatment
- Date Crossref
- 07/02/2025
- Éditeur
- Public Library of Science (PLoS)
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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Henry Ford Health pays non établi dans la noticeOrganisation à but non lucratif
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Wayne State University Department of Oncology pays non établi dans la noticeUniversité ou école supérieure
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Michigan United pays non établi dans la noticeOrganisation à but non lucratif
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George Mason University Center for Applied Proteomics and Molecular Medicine pays non établi dans la noticeUniversité ou école supérieure
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Michigan State University pays non établi dans la noticeUniversité ou école supérieure
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Department of Neurosurgery pays non établi dans la noticeInstitution
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Department of Radiation Oncology pays non établi dans la noticeInstitution
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Precision Medicine Program pays non établi dans la noticeInstitution
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Department of Public Health pays non établi dans la noticeInstitution
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School of Medicine Department of Obstetrics and Gynecology pays non établi dans la noticeUniversité ou école supérieure
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College of Human Medicine Department of Physiology pays non établi dans la noticeUniversité ou école supérieure
Henry Ford Health, Department of Oncology — Wayne State University et Michigan United, avec 8 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.