Genomic exploration of distinct molecular phenotypes steering temozolomide resistance development in patient-derived glioblastoma cells
Chemotherapy using temozolomide is the standard treatment for patients with glioblastoma. Despite treatment, prognosis is still poor largely due to the emergence of temozolomide resistance. This resistance is closely linked to the widely recognized inter- and intra-tumoral heterogeneity in glioblastoma, although the underlying mechanisms are not yet fully understood. To induce temozolomide resistance, we subjected 21 patient-derived glioblastoma cell cultures to Temozolomide treatment for a period of up to 90 days. Prior to treatment, the cells' molecular characteristics were analyzed using bulk RNA sequencing. Additionally, we performed single-cell RNA sequencing on four of the cell cultures to track the evolution of temozolomide resistance. The induced temozolomide resistance was associated with two distinct phenotypic behaviors, classified as "adaptive" (ADA) or "non-adaptive" (N-ADA) to temozolomide. The ADA phenotype displayed neurodevelopmental and metabolic gene signatures, whereas the N-ADA phenotype expressed genes related to cell cycle regulation, DNA repair, and protein synthesis. Single-cell RNA sequencing revealed that in ADA cell cultures, one or more subpopulations emerged as dominant in the resistant samples, whereas N-ADA cell cultures remained relatively stable. The adaptability and heterogeneity of glioblastoma cells play pivotal roles in temozolomide treatment and contribute to the tumor's ability to survive. Depending on the tumor's adaptability potential, subpopulations with acquired resistance mechanisms may arise.
Funding
European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie ITN initiative (Grant Agreement #766069)
History
Data Availability Statement
Bulk RNA sequencing data of the cell lines (n = 21) applied in this article is available in the Gene Expression Omnibus Repository with Accession number GSE232173. Single-cell RNA sequencing data is available in the Gene Expression Omnibus Repository with Accession number: GSE226202.Comments
The original article is available at https://www.mdpi.com/Published Citation
Fabro F, et al. Genomic exploration of distinct molecular phenotypes steering temozolomide resistance development in patient-derived glioblastoma cells. Int J Mol Sci. 2023;24(21):15678.Publication Date
27 October 2023External DOI
PubMed ID
37958662Department/Unit
- Physiology and Medical Physics
Publisher
MDPIVersion
- Published Version (Version of Record)