Amodeo, Valeria; Davies, Timothy; Martinez-Segura, Amalia; Clements, Melanie; Ragdale, Holly Simpson; Bailey, Andrew; Silva Dos Santos, Mariana; ... Parrinello, Simona; + view all Amodeo, Valeria; Davies, Timothy; Martinez-Segura, Amalia; Clements, Melanie; Ragdale, Holly Simpson; Bailey, Andrew; Silva Dos Santos, Mariana; MacRae, James; Mokochinski, Joao; Kramer, Holger; Garcia-Diaz, Claudia; Gould, Alex; Marguerat, Samuel; Parrinello, Simona; - view fewer (2022) Diet suppresses tumour initiation by maintaining quiescence of mutation-bearing neural stem cells. bioRxiv: Cold Spring Harbor, NY, USA.

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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.

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