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.

致癌PIK3CA突变会在衰老的人类食道中产生大量克隆。在这里，我们研究了Pik3ca突变克隆在转基因小鼠正常食管上皮中的行为。杂合Pik3ca ^H1047R突变的表达通过使细胞命运向增殖倾斜来驱动克隆扩增。对原代食管角质形成细胞的 CRISPR 筛选和抑制剂处理证实了 PI3K-mTOR 通路增加了突变细胞的竞争适应性。抗糖尿病药物二甲双胍降低了突变细胞在体内和体外的优势。相反，1 型糖尿病或饮食引起的肥胖等代谢状况增强了Pik3ca ^H1047R细胞的竞争适应性。一致地，我们发现与体重正常的个体相比，高体重指数个体的食道中PIK3CA功能获得性突变的密度更高。我们得出的结论是，代谢环境选择性地影响正常上皮突变景观的进化。临床上可行的干预措施可以平衡野生型和突变细胞之间的信号失衡，可能会限制致癌突变体在正常组织中的扩张。