Recommended Citation
Berezovsky A, Nuga O, Datta I, Bergman K, Sabedot T, Gurdziel K, Irtenkauf S, Hasselbach L, Meng Y, Mueller C, Petricoin EF, 3rd, Brown S, Purandare N, Aras S, Mikkelsen T, Poisson L, Noushmehr H, Ruden D, and deCarvalho AC. Impact of developmental state, p53 status, and interferon signaling on glioblastoma cell response to radiation and temozolomide treatment. PLoS One 2025; 20(2):e0315171.
Document Type
Article
Publication Date
2-7-2025
Publication Title
PLoS One
Abstract
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.
Medical Subject Headings
Humans; Temozolomide; Glioblastoma; Tumor Suppressor Protein p53; Signal Transduction; Neoplastic Stem Cells; Cell Line, Tumor; Interferons; Dacarbazine; Antineoplastic Agents, Alkylating; Brain Neoplasms; DNA Methylation; Cell Differentiation; Gene Expression Regulation, Neoplastic; DNA Modification Methylases; NF-kappa B; Drug Resistance, Neoplasm; DNA Repair Enzymes; Tumor Suppressor Proteins
PubMed ID
39919036
Volume
20
Issue
2
First Page
0315171
Last Page
0315171
