Glioblastoma Stem Cells Respond to Differentiation Cues but Fail to Undergo Commitment and Terminal Cell-Cycle Arrest
Helena Carén1, Stefan H Stricker2, Harry Bulstrode3
1Department of Cancer Biology, UCL Cancer Institute, University College London, Paul O'Gorman Building, 72 Huntley Street, London WC1E 6BT, UK; Sahlgrenska Cancer Center, Department of Pathology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, 405 30 Gothenburg, Sweden; Samantha Dickson Brain Cancer Unit, University College London, London WC1E 6BT, UK.
Abstract:
Glioblastoma (GBM) is an aggressive brain tumor whose growth is driven by stemcell-like cells. BMP signaling triggers cell-cycle exit and differentiation of GBM stemcells (GSCs) and, therefore, might have therapeutic value. However, the epigenetic mechanisms that accompany differentiation remain poorly defined. It is also unclear whether cell-cycle arrest is terminal. Herewe find only a subset ofGSCcultures exhibit astrocyte differentiation in response to BMP. Although overtly differentiated non-cycling astrocytes are generated, they remain vulnerable to cell-cycle re-entry and fail to appropriately reconfigure DNA methylation patterns. Chromatin accessibility mapping identified loci that failed to alter in response to BMP and these were enriched in SOX transcription factor-binding motifs. SOX transcription factors, therefore, may limit differentiation commitment. A similar propensity for cell-cycle re-entry and de-differentiation was observed in GSC-derived oligodendrocyte-like cells. These findings highlight significant obstacles to BMP-induced differentiation as therapy forGBM.
Insights
Bone morphogenetic protein (BMP) signaling can trigger glioblastoma stem cell (GSC) differentiation, but epigenetic changes and sustained cell-cycle exit remain challenging for GBM therapy.
Area of Science:
- Neuro-oncology
- Cancer Stem Cell Biology
- Epigenetics
Background:
- Glioblastoma (GBM) growth is driven by stem-like cells.
- BMP signaling can induce GBM stem cell (GSC) differentiation and cell-cycle exit, suggesting therapeutic potential.
- Epigenetic mechanisms and terminal differentiation in response to BMP are not well understood.
Purpose of the Study:
- To investigate the epigenetic mechanisms accompanying BMP-induced GSC differentiation.
- To determine if BMP-induced cell-cycle arrest is terminal in GSCs.
- To identify factors limiting differentiation commitment.
Main Methods:
- Cultured GSC lines treated with BMP.
- Analysis of cell-cycle status and differentiation markers.
- DNA methylation pattern analysis.
- Chromatin accessibility mapping (ATAC-seq).
Main Results:
- Only a subset of GSC cultures differentiated upon BMP treatment.
- Differentiated astrocytes re-entered the cell cycle and failed to properly reconfigure DNA methylation.
- Chromatin accessibility mapping revealed SOX transcription factor-binding motifs at loci resistant to change.
- GSC-derived oligodendrocyte-like cells also showed de-differentiation.
Conclusions:
- BMP-induced differentiation faces significant obstacles in glioblastoma.
- Sustained cell-cycle exit and epigenetic reprogramming are not reliably achieved.
- SOX transcription factors may impede differentiation commitment in GSCs.
More Related Videos
09:36Live-Cell Imaging Assays to Study Glioblastoma Brain Tumor Stem Cell Migration and Invasion
Published on: August 29, 2018
12:25Optimization of High Grade Glioma Cell Culture from Surgical Specimens for Use in Clinically Relevant Animal Models and 3D Immunochemistry
Published on: January 7, 2014
Related Concept Videos
02:40Cancer Stem Cells and Tumor Maintenance
Cancer stem cells are thought to originate from tissue-specific normal stem cells or progenitor cells. The normal stem cells usually reside in...
01:26Stem Cell Niche
01:06Multipotency and Niche of Bulge Stem Cell
01:18Distinctive Features of Adult Stem Cells vs Cancer Stem Cells
Adult stem cells
Adult stem cells are tissue-specific; hence, they divide to develop the tissue from which they originate. One type of adult stem cell is the epithelial stem cell, which gives rise to the keratinocytes in the multiple layers of epithelial cells in the epidermis of the skin. Adult bone marrow has three distinct types of stem cells:...