Aberrant mesenchymal differentiation of glioma stem-like cells: implications for therapeutic targeting
Veerakumar Balasubramaniyan1,2,3, Brian Vaillant1,2, Shuzhen Wang1,2
1Department of Neuro-Oncology, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA.
Abstract:
Differentiation has been proposed as a therapeutic strategy for glioblastoma (GBM) in part due to observations of stem-like cells in GBM that have been shown to undergo terminal differentiation in response to growth factor withdrawal and BMP activation. However, the effects of long term exposure to serum culture conditions on glioma sphere cultures/glioma stem-like cells (GSCs) have not been examined. Here we show that GSCs retained both neurosphere formation and tumor initiation abilities after short or long term serum exposure. Under these conditions, GSCs expressed both neural lineage and stem cell markers, highlighting the aberrant pseudo-differentiation state. GSCs maintained under adherent serum cultured conditions continued to proliferate and initiate tumor formation with efficiencies similar to GSCs maintained under proliferating (neurosphere) conditions. Proneural (PN) GSCs under serum exposure showed an induction of mesenchymal (MES) gene expression signatures. Our data indicate that exposure to serum containing media result in aberrant differentiation (e.g. toward MES lineage) and activation of alternative oncogenic pathways in GSCs.
Insights
Glioma stem-like cells (GSCs) maintain tumor-forming abilities even after long-term serum exposure, indicating they do not terminally differentiate as expected. Serum exposure promotes aberrant differentiation and activates alternative oncogenic pathways in these glioblastoma cells.
Area of Science:
- Neuroscience
- Cancer Biology
- Stem Cell Research
Background:
- Glioblastoma (GBM) therapeutic strategies explore differentiation of glioblastoma stem-like cells (GSCs).
- Previous studies suggested GSCs differentiate upon growth factor withdrawal or BMP activation.
- Long-term effects of serum culture on GSCs remain largely unexamined.
Purpose of the Study:
- To investigate the impact of short and long-term serum exposure on GSC properties.
- To determine if GSCs undergo terminal differentiation under serum culture conditions.
- To analyze gene expression changes and oncogenic pathway activation in GSCs exposed to serum.
Main Methods:
- Culturing GSCs under serum-containing conditions (adherent and neurosphere).
- Assessing neurosphere formation and tumor initiation capabilities.
- Analyzing expression of neural lineage and stem cell markers.
- Evaluating gene expression signatures (e.g., proneural and mesenchymal).
Main Results:
- GSCs retained neurosphere formation and tumor initiation abilities after short or long-term serum exposure.
- Serum-exposed GSCs exhibited aberrant pseudo-differentiation, expressing both neural and stem cell markers.
- Proneural GSCs showed induced mesenchymal gene expression signatures under serum exposure.
- GSCs in adherent serum culture proliferated and initiated tumors similarly to neurosphere cultures.
Conclusions:
- Serum exposure does not induce terminal differentiation in GSCs.
- GSCs can maintain stemness and tumorigenicity under prolonged serum conditions.
- Serum exposure leads to aberrant differentiation (e.g., mesenchymal lineage) and activates alternative oncogenic pathways in GSCs.
Related Concept Videos
01:19Mesenchymal Stem Cells
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...