Organismal 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<sup>H1047R</sup> 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<sup>H1047R</sup> 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.
Authors
- Charlotte King (ORCID: https://orcid.org/0000-0003-2543-1993)
- Christian Frezza (ORCID: https://orcid.org/0000-0002-3293-7397)
- Michael Hall (ORCID: https://orcid.org/0000-0003-2904-6902)
- Argyro Kalogeropoulou
- Swee Hoe Ong (ORCID: https://orcid.org/0000-0002-3629-5387)
- Gabriel Piedrafita (ORCID: https://orcid.org/0000-0001-8701-1084)
- Chris Bryant (ORCID: https://orcid.org/0000-0001-7744-3596)
- Bartomeu Colom (ORCID: https://orcid.org/0000-0001-6256-6462)
- Philip H. Jones (ORCID: https://orcid.org/0000-0002-5904-795X)
- Joanna C. Fowler (ORCID: https://orcid.org/0000-0001-7546-369X)
- Albert Herms (ORCID: https://orcid.org/0000-0003-2999-8196)
- Bart Vanhaesebroeck (ORCID: https://orcid.org/0000-0002-7074-3673)
- Ujjwal Banerjee
- Albert Pol (ORCID: https://orcid.org/0000-0002-1750-1085)
- Roshan Sood (ORCID: https://orcid.org/0000-0002-1318-7025)
- Emilie Abby (ORCID: https://orcid.org/0000-0003-0284-4760)
- David Fernández‐Antorán (ORCID: https://orcid.org/0000-0003-1608-570X)
- I. Caseda
- Kasumi Murai
Institutions
- Institució Catalana de Recerca i Estudis Avançats (ES)
- Universidad Complutense de Madrid (ES)
- University of Cambridge (GB)
- The Gurdon Institute (GB)
- Wellcome Sanger Institute (GB)
- Spanish National Cancer Research Centre (ES)
- Hutchison/MRC Research Centre (GB)
- Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (DE)
- CRUK Lung Cancer Centre of Excellence (GB)
- Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES)
- University College London (GB)
- Universitat de Barcelona (ES)
Publication Details
- Journal
- Nature Genetics
- Published
- 2024-08-21
- DOI
- https://doi.org/10.1038/s41588-024-01891-8
- Citations
- 21
- Primary Topic
- Pancreatic and Hepatic Oncology Research
- Type
- article
- Field-Weighted Citation Impact
- 5.93
Funders
- European Molecular Biology Organization
- Wellcome
- Cancer Research UK
- Agencia Estatal de Investigación