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Diet suppresses tumour initiation by maintaining quiescence of mutation-bearing neural stem cells

Amodeo, Valeria; Davies, Timothy; Martinez-Segura, Amalia; Clements, Melanie; Ragdale, Holly Simpson; Bailey, Andrew; Silva Dos Santos, Mariana; ... Parrinello, Simona; + view all (2022) Diet suppresses tumour initiation by maintaining quiescence of mutation-bearing neural stem cells. bioRxiv: Cold Spring Harbor, NY, USA. Green open access

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Abstract

Glioblastoma is thought to originate from neural stem cells (NSCs) of the subventricular zone that acquire genetic alterations. In the adult brain, NSCs are largely quiescent, suggesting that deregulation of quiescence maintenance may be a pre-requisite for tumour initiation. Although inactivation of the tumour suppressor p53 is a frequent event in gliomagenesis, whether, or how, it affects quiescent NSCs (qNSCs) remains unclear. Here we show that p53 maintains quiescence by inducing fatty acid oxidation (FAO) and that acute p53 deletion in qNSCs results in their premature activation to a proliferative state. Mechanistically, this occurs through direct transcriptional induction of PPARGC1a, which in turn activates PPARα to upregulate FAO genes. Strikingly, dietary supplementation with fish oil containing omega-3 fatty acids, natural PPARα ligands, fully restores quiescence of p53-deficient NSCs and delays tumour initiation in a glioblastoma mouse model. Thus, diet can silence glioblastoma driver mutations, with important implications for cancer prevention.

Type: Working / discussion paper
Title: Diet suppresses tumour initiation by maintaining quiescence of mutation-bearing neural stem cells
Open access status: An open access version is available from UCL Discovery
DOI: 10.1101/2022.03.09.483611
Publisher version: https://doi.org/10.1101/2022.03.09.483611
Language: English
Additional information: The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license (https://creativecommons.org/licenses/by-nc-nd/4.0/).
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Cancer Bio
URI: https://discovery.ucl.ac.uk/id/eprint/10160563
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