Ribogenesis boosts controlled by HEATR1-MYC interplay promote transition into brain tumour growth

Abstract

<jats:title>Abstract</jats:title><jats:p>Cell commitment to tumourigenesis and the onset of uncontrolled growth are critical determinants in cancer development but the early events directing tumour initiating cell (TIC) fate remain unclear. We reveal a single-cell transcriptome profile of brain TICs transitioning into tumour growth using the <jats:italic>brain tumour</jats:italic> (<jats:italic>brat</jats:italic>) neural stem cell-based <jats:italic>Drosophila</jats:italic> model. Prominent changes in metabolic and proteostasis-associated processes including ribogenesis are identified. Increased ribogenesis is a known cell adaptation in established tumours. Here we propose that brain TICs boost ribogenesis prior to tumour growth. In <jats:italic>brat-</jats:italic>deficient TICs, we show that this dramatic change is mediated by upregulated <jats:italic>HEAT-Repeat Containing 1</jats:italic> (<jats:italic>HEATR1</jats:italic>) to promote ribosomal RNA generation, TIC enlargement and onset of overgrowth. High <jats:italic>HEATR1</jats:italic> expression correlates with poor glioma patient survival and patient-derived glioblastoma stem cells rely on HEATR1 for enhanced ribogenesis and tumourigenic potential. Finally, we show that HEATR1 binds the master growth regulator MYC, promotes its nucleolar localisation and appears required for MYC-driven ribogenesis, suggesting a mechanism co-opted in ribogenesis reprogramming during early brain TIC development.</jats:p>