英国威康桑格研究所Philip H. Jones团队近期取得重要工作进展，他们研究提出，生物体代谢能够调节正常食管中致癌PIK3CA突变克隆的扩增。相关研究成果2024年8月21日在线发表于《自然—遗传学》杂志上。

据介绍，致癌PIK3CA突变在衰老的人类食管细胞中产生大量克隆。

研究人员探讨了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突变的表达通过将细胞命运向增殖倾斜来驱动克隆扩增。对原发性食管角质形成细胞进行CRISPR筛选和抑制剂处理证实，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，代谢状况，如1型糖尿病或饮食诱导的肥胖，增强了Pik3ca^H1047R细胞的竞争适应性。一致地，研究人员发现与体重正常的人相比，体重指数高的人食管中PIK3CA功能获得突变的密度更高。

总之，这一研究表明，代谢环境选择性地影响正常上皮突变概况的演变。临床上可行的干预措施，以平衡野生型和突变型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。

附：英文原文

Title: Organismal metabolism regulates the expansion of oncogenic PIK3CA mutant clones in normal esophagus

Author: Herms, Albert, Colom, Bartomeu, Piedrafita, Gabriel, Kalogeropoulou, Argyro, Banerjee, Ujjwal, King, Charlotte, Abby, Emilie, Murai, Kasumi, Caseda, Irene, Fernandez-Antoran, David, Ong, Swee Hoe, Hall, Michael W. J., Bryant, Christopher, Sood, Roshan K., Fowler, Joanna C., Pol, Albert, Frezza, Christian, Vanhaesebroeck, Bart, Jones, Philip H.

Issue&Volume: 2024-08-21

Abstract: 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 Pik3caH1047R 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 Pik3caH1047R 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.

DOI: 10.1038/s41588-024-01891-8

Source: https://www.nature.com/articles/s41588-024-01891-8