ASCL1 phosphorylation and ID2 upregulation are roadblocks to glioblastoma stem cell differentiation
Roberta Azzarelli1,2,3, Aoibheann McNally4,5, Claudia Dell'Amico6
1Wellcome - Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK. ra605@cam.ac.uk.
Abstract:
The growth of glioblastoma (GBM), one of the deadliest adult cancers, is fuelled by a subpopulation of stem/progenitor cells, which are thought to be the source of resistance and relapse after treatment. Re-engagement of a latent capacity of these cells to re-enter a trajectory resulting in cell differentiation is a potential new therapeutic approach for this devastating disease. ASCL1, a proneural transcription factor, plays a key role in normal brain development and is also expressed in a subset of GBM cells, but fails to engage a full differentiation programme in this context. Here, we investigated the barriers to ASCL1-driven differentiation in GBM stem cells. We see that ASCL1 is highly phosphorylated in GBM stem cells where its expression is compatible with cell proliferation. However, overexpression of a form of ASCL1 that cannot be phosphorylated on Serine-Proline sites drives GBM cells down a neuronal lineage and out of cell cycle more efficiently than its wild-type counterpart, an effect further enhanced by deletion of the inhibitor of differentiation ID2, indicating mechanisms to reverse the block to GBM cell differentiation.
Insights
Targeting glioblastoma stem cells involves re-engaging their differentiation capacity. Modifying the ASCL1 transcription factor by preventing phosphorylation enhances this differentiation, offering a new therapeutic strategy for glioblastoma.
Area of Science:
- Neuro-oncology
- Cancer Stem Cell Biology
- Molecular Neuroscience
Background:
- Glioblastoma (GBM) growth is driven by stem/progenitor cells, contributing to treatment resistance and relapse.
- Re-engaging the differentiation capacity of these cells presents a potential therapeutic avenue for GBM.
- ASCL1, a proneural transcription factor, is expressed in GBM but does not fully induce differentiation.
Purpose of the Study:
- Investigate the barriers to ASCL1-driven differentiation in glioblastoma stem cells.
- Determine if modifying ASCL1 phosphorylation can overcome differentiation block.
- Explore the role of ID2 in ASCL1-mediated differentiation.
Main Methods:
- Analyzed ASCL1 phosphorylation status in GBM stem cells.
- Overexpressed wild-type and non-phosphorylatable mutant ASCL1 in GBM cells.
- Assessed the effect of ASCL1 modifications and ID2 deletion on cell differentiation and cell cycle exit.
Main Results:
- ASCL1 is highly phosphorylated in proliferating GBM stem cells.
- Overexpression of non-phosphorylatable ASCL1 enhanced neuronal differentiation and cell cycle exit.
- Deletion of the differentiation inhibitor ID2 further promoted ASCL1-driven differentiation.
Conclusions:
- ASCL1 phosphorylation acts as a barrier to differentiation in glioblastoma stem cells.
- Targeting ASCL1 phosphorylation is a promising strategy to induce GBM cell differentiation.
- Inhibiting ID2 may synergize with ASCL1 modulation for GBM therapy.
