biostudies-literatureHerms AEuropean Molecular Biology OrganizationCancer Research UKEuropean Molecular Biology Organization (EMBO)Maria Zambrano Grant to attract international talent from Universitat de Barcelona and Ministerio de Universidades, cofunded with Next Generation EU fundsMinistry of Economy and Competitiveness | Agencia Estatal de InvestigaciónMinistry of Economy and Competitiveness | Agencia Estatal de Investigación (Spanish Agencia Estatal de Investigación)Wellcome Trust2144-2157https://www.ebi.ac.uk/biostudies/studies/S-EPMC11525199biostudies-literatureUnknown56(10)Oncogenic PIK3CA mutations generate large clones in aging human esophagus. Here we investigate the behavior of Pik3ca mutant clones in the normal esophageal epithelium of transgenic mice. Expression of a heterozygous Pik3ca^H1047R mutation drives clonal expansion by tilting cell fate toward proliferation. CRISPR screening and inhibitor treatment of primary esophageal keratinocytes confirmed the PI3K-mTOR pathway increased mutant cell competitive fitness. The antidiabetic drug metformin reduced mutant cell advantage in vivo and in vitro. Conversely, metabolic conditions such as type 1 diabetes or diet-induced obesity enhanced the competitive fitness of Pik3ca^H1047R cells. Consistently, we found a higher density of PIK3CA gain-of-function mutations in the esophagus of individuals with high body mass index compared with those with normal weight. We conclude that the metabolic environment selectively influences the evolution of the normal epithelial mutational landscape. Clinically feasible interventions to even out signaling imbalances between wild-type and mutant cells may limit the expansion of oncogenic mutants in normal tissues.Nature geneticsOrganismal metabolism regulates the expansion of oncogenic PIK3CA mutant clones in normal esophagus.PMC11525199PID2020-116163GA-I00296194C23338/A25722098051C609/A17257EMBO ALTF885-2015C609/A27326108413/A/15/DOng SHBanerjee UJones PHAbby EFowler JCMurai KHall MWJKalogeropoulou AFrezza CPiedrafita GKing CHerms ACaseda IColom BSood RKPol ABryant CFernandez-Antoran DVanhaesebroeck BfalseOrganismal metabolism regulates the expansion of oncogenic PIK3CA mutant clones in normal esophagus.Oncogenic PIK3CA mutations generate large clones in aging human esophagus. Here we investigate the behavior of Pik3ca mutant clones in the normal esophageal epithelium of transgenic mice. Expression of a heterozygous Pik3ca^H1047R mutation drives clonal expansion by tilting cell fate toward proliferation. CRISPR screening and inhibitor treatment of primary esophageal keratinocytes confirmed the PI3K-mTOR pathway increased mutant cell competitive fitness. The antidiabetic drug metformin reduced mutant cell advantage in vivo and in vitro. Conversely, metabolic conditions such as type 1 diabetes or diet-induced obesity enhanced the competitive fitness of Pik3ca^H1047R cells. Consistently, we found a higher density of PIK3CA gain-of-function mutations in the esophagus of individuals with high body mass index compared with those with normal weight. We conclude that the metabolic environment selectively influences the evolution of the normal epithelial mutational landscape. Clinically feasible interventions to even out signaling imbalances between wild-type and mutant cells may limit the expansion of oncogenic mutants in normal tissues.2024-01-01T00:00:00Z2024 Oct2025-04-04T22:47:47.84Z2025-04-04T22:47:47.84ZS-EPMC115251993916925910.1038/s41588-024-01891-8