Shared molecular regulation of quiescence in neural and glioma stem cells reveals therapeutic vulnerabilities.

Quiescence, a reversible state of cell-cycle arrest, is an adaptive feature of many adult tissue stem cells, including those in the adult brain. In gliomas, brain tumour stem cells that reside in a quiescent state preferentially survive chemotherapy and radiotherapy, highlighting their critical role in therapy resistance and disease progression. To date, it remains unclear whether the molecular programs governing these states are functionally conserved between neural stem cells and brain tumour stem cells. Here, we establish novel in vitro models to study quiescence and find that glioma stem cells are markedly more resistant to entering quiescence than neural stem cells, suggesting that glioma stem cell quiescence more closely resembles a slow-cycling phenotype or shallow quiescence. Nonetheless, direct comparison of quiescent neural stem cells and quiescent/slow-cycling glioma stem cells, as they transition towards proliferation, reveals conserved gene expression trajectories, indicating shared molecular mechanisms. Furthermore, we find that pathways influencing quiescence in neural stem cells exert similar effects in glioma stem cells, underscoring the functional parallels between these populations. Finally, we identify that inhibition of TGF-beta signalling might provide an avenue to improve current standard-of-care treatments by targeting quiescent glioma stem cells.