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Identification and Isolation of Slow-Dividing Cells in Human Glioblastoma Using Carboxy Fluorescein Succinimidyl Ester CFSE
Published on: April 29, 2012
Decoding key cell sub-populations and molecular alterations in glioblastoma at recurrence by single-cell analysis
Xin Wang1,2, Qian Sun1, Weiwen Wang3
1RNA Institute, Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, 430072, China.
Abstract:
Glioblastoma (GBM) is the most frequent malignant brain tumor, the relapse of which is unavoidable following standard treatment. However, the effective treatment for recurrent GBM is lacking, necessitating the understanding of key mechanisms driving tumor recurrence and the identification of new targets for intervention. Here, we integrated single-cell RNA-sequencing data spanning 36 patient-matched primary and recurrent GBM (pGBM and rGBM) specimens, with 6 longitudinal GBM spatial transcriptomics to explore molecular alterations at recurrence, with each cell type characterized in parallel. Genes involved in extracellular matrix (ECM) organization are preferentially enriched in rGBM cells, and MAFK is highlighted as a potential regulator. Notably, we uncover a unique subpopulation of GBM cells that is much less detected in pGBM and highly expresses ECM and mesenchyme related genes, suggesting it may contribute to the molecular transition of rGBM. Further regulatory network analysis reveals that transcription factors, such as NFATC4 and activator protein 1 members, may function as hub regulators. All non-tumor cells alter their specific sets of genes as well and certain subgroups of myeloid cells appear to be physically associated with the mesenchyme-like GBM subpopulation. Altogether, our study provides new insights into the molecular understanding of GBM relapse and candidate targets for rGBM treatment.
Insights
Recurrent glioblastoma (GBM) shows enriched extracellular matrix genes, with a novel mesenchymal subpopulation driving relapse. Understanding these mechanisms offers new therapeutic targets for brain tumors.
Area of Science:
- Neuro-oncology
- Genomics
- Molecular Biology
Background:
- Glioblastoma (GBM) is the most common malignant brain tumor.
- Tumor relapse is unavoidable after standard treatment, with limited options for recurrent GBM (rGBM).
- Understanding GBM recurrence mechanisms is crucial for identifying new therapeutic targets.
Purpose of the Study:
- To explore molecular alterations driving glioblastoma recurrence.
- To identify novel therapeutic targets for recurrent glioblastoma.
- To characterize cell-type-specific changes from primary to recurrent GBM.
Main Methods:
- Integrated single-cell RNA-sequencing from 36 patient-matched primary and recurrent GBM specimens.
- Utilized 6 longitudinal GBM spatial transcriptomics datasets.
- Analyzed gene expression and regulatory networks in individual cell types.
Main Results:
- Extracellular matrix (ECM) organization genes are preferentially enriched in recurrent GBM (rGBM) cells.
- A unique subpopulation of GBM cells, highly expressing ECM and mesenchymal genes, is identified in rGBM.
- Transcription factors like NFATC4 and AP-1 members are identified as potential hub regulators.
- Non-tumor cells, particularly myeloid cells, also show altered gene expression and association with mesenchymal GBM cells.
Conclusions:
- The study provides new insights into the molecular mechanisms of GBM relapse.
- A mesenchymal-like GBM subpopulation may drive tumor transition and recurrence.
- Identified molecular pathways and transcription factors represent potential therapeutic targets for rGBM.
