Rita Sousa-Nunes’ laboratory was awarded a Brain Research UK Grant (including a postdoc position for three years) to investigate “Neural tumour anachronism”. Neural stem cell generation of diverse cell types is underpinned by spatial and temporal patterning of progenitors. Temporal patterning consists of sequentially expressed transcription factors that dictate progeny identity over time. The Sousa-Nunes laboratory and others have shown that, in Drosophila, this so-called temporal series also regulates stem cell behaviours like quiescence (reversible proliferation arrest), termination (irreversible proliferation arrest), and malignancy. Their laboratory and that of their collaborators (Maurange laboratory in Marseille) found that Drosophila neural tumour-suppressor mutations are only malignant if induced within an early time window. Tumour-suppressor mutations induced late lead to hyperplasia but not cancer since all supernumerary stem cells express late temporal factors and can terminate divisions accordingly. Tumours induced early contain heterogeneous stem cell populations at late stages, most having progressed through the temporal series to an “older” state but a subset retaining a “young” molecular signature. Only the stem cells “locked” in an early developmental/temporal program are cancer stem cells (CSCs) since expression of early temporal factors is necessary for malignancy. A fraction of these CSCs exhibit molecular hallmarks of cell-cycle inhibition, suggesting they may be quiescent. They will exploit well-defined and exquisitely controllable Drosophila models as a unique opportunity to test the novel hypothesis that quiescence blocks the temporal progression of neural tumour cells, thus generating CSCs.
Strikingly, the molecular network that mediates malignancy in Drosophila neural tumours is frequently deregulated in paediatric brain tumours. Given the evolutionary conservation of cellular and molecular hierarchies and pathways at play in neural tumour formation, their findings in Drosophila will prompt future work in mammalian models (e.g., mouse in vivo and human brain organoids). Their vision is to establish a strong foundation of understanding from which to spring-board quiescence perturbation as a novel therapeutic intervention for glioblastoma treatment.