ASCL1 phosphorylation and ID2 upregulation are roadblocks to glioblastoma stem cell differentiation.
Nature Publishing Group
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Azzarelli, R., McNally, A., Dell'Amico, C., Onorati, M., Simons, B., & Philpott, A. (2022). ASCL1 phosphorylation and ID2 upregulation are roadblocks to glioblastoma stem cell differentiation.. Sci Rep https://doi.org/10.1038/s41598-022-06248-x
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.
Wellcome Trust (203151/A/16/Z)
Wellcome Trust (098357/Z/12/Z)
Cancer Research UK (A25636)
Wellcome Trust (212253/Z/18/Z)
Wellcome Trust (203151/Z/16/Z)
Medical Research Council (MC_PC_17230)
External DOI: https://doi.org/10.1038/s41598-022-06248-x
This record's URL: https://www.repository.cam.ac.uk/handle/1810/332880
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/