Amodeo, Valeria; Davies, Timothy; Martinez-Segura, Amalia; Clements, Melanie P; Ragdale, Holly Simpson; Bailey, Andrew; Dos Santos, Mariana Silva; ... Parrinello, Simona; + view all Amodeo, Valeria; Davies, Timothy; Martinez-Segura, Amalia; Clements, Melanie P; Ragdale, Holly Simpson; Bailey, Andrew; Dos Santos, Mariana Silva; MacRae, James I; Mokochinski, Joao; Kramer, Holger; Garcia-Diaz, Claudia; Gould, Alex P; Marguerat, Samuel; Parrinello, Simona; - view fewer (2023) Diet suppresses glioblastoma initiation in mice by maintaining quiescence of mutation-bearing neural stem cells. Developmental Cell 10.1016/j.devcel.2023.03.021. (In press).

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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 prerequisite for tumor initiation. Although inactivation of the tumor 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. Dietary supplementation with fish oil containing omega-3 fatty acids, natural PPARα ligands, fully restores quiescence of p53-deficient NSCs and delays tumor initiation in a glioblastoma mouse model. Thus, diet can silence glioblastoma driver mutations, with important implications for cancer prevention.

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