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ASCL1 phosphorylation and ID2 upregulation are roadblocks to glioblastoma stem cell differentiation

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Azzarelli, Roberta 
McNally, Aoibheann 
Dell’Amico, Claudia 
Onorati, Marco 
Simons, Benjamin 


jats:titleAbstract</jats:title>jats:pThe 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.</jats:p>



Article, /631/67, /631/80, /631/136, /631/532, article

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Scientific Reports

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Springer Science and Business Media LLC
Society for Developmental Biology ('Innovation Grant')
Ministero dell’Istruzione, dell’Università e della Ricerca ('Rita Levi Montalcini' program)
Cancer Research UK (Studentship, A25636)
Ministero della Salute (GR-2018-12367290)
Wellcome Trust (098357/Z/12/Z, 212253/Z/18/Z)
Royal Society (RP\R1\180165)