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

Author:

Diaz Laura R,Gil-Ranedo JonORCID,Jaworek Karolina JORCID,Nsek NsikanORCID,Marques Joao PinheiroORCID,Costa Eleni,Hilton David A,Bieluczyk Hubert,Warrington Oliver,Hanemann C OliverORCID,Futschik Matthias EORCID,Bossing TorstenORCID,Barros Claudia SORCID

Abstract

AbstractCell 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 brain tumour (brat) neural stem cell-based Drosophila 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 brat-deficient TICs, we show that this dramatic change is mediated by upregulated HEAT-Repeat Containing 1 (HEATR1) to promote ribosomal RNA generation, TIC enlargement and onset of overgrowth. High HEATR1 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.

Funder

Tenovus

Brain Research UK

Brain Tumour Research

University of Plymouth

Publisher

Springer Science and Business Media LLC

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