Children's Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine, Children's Research Institute Mouse Genome Engineering Core, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Quantitative Biomedical Research Center, Peter O'Donnell Jr. School of Public Health, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Division of Pediatric Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Department of Pediatrics, University of Cincinnati, Cincinnati, OH 45229, USA.
Cell Metab. 2024 Aug 6;36(8):1711-1725.e8. doi: 10.1016/j.cmet.2024.05.015. Epub 2024 Jun 19.
Somatic mutations in non-malignant tissues are selected for because they confer increased clonal fitness. However, it is uncertain whether these clones can benefit organ health. Here, ultra-deep targeted sequencing of 150 liver samples from 30 chronic liver disease patients revealed recurrent somatic mutations. PKD1 mutations were observed in 30% of patients, whereas they were only detected in 1.3% of hepatocellular carcinomas (HCCs). To interrogate tumor suppressor functionality, we perturbed PKD1 in two HCC cell lines and six in vivo models, in some cases showing that PKD1 loss protected against HCC, but in most cases showing no impact. However, Pkd1 haploinsufficiency accelerated regeneration after partial hepatectomy. We tested Pkd1 in fatty liver disease, showing that Pkd1 loss was protective against steatosis and glucose intolerance. Mechanistically, Pkd1 loss selectively increased mTOR signaling without SREBP-1c activation. In summary, PKD1 mutations exert adaptive functionality on the organ level without increasing transformation risk.
非恶性组织中的体细胞突变是被选择的，因为它们赋予了更高的克隆适应性。然而，目前还不确定这些克隆是否能有益于器官健康。在这里，对 30 名慢性肝病患者的 150 个肝脏样本进行了超深度靶向测序，揭示了反复出现的体细胞突变。PKD1 突变在 30%的患者中被观察到，而在肝癌（HCC）中仅检测到 1.3%。为了探究肿瘤抑制因子的功能，我们在两种 HCC 细胞系和六种体内模型中干扰了 PKD1，在某些情况下表明 PKD1 缺失可以预防 HCC，但在大多数情况下没有影响。然而，Pkd1 半合子缺失加速了肝部分切除后的再生。我们在脂肪性肝病中测试了 Pkd1，结果表明 Pkd1 缺失可以预防脂肪变性和葡萄糖不耐受。从机制上讲，Pkd1 缺失选择性地增加了 mTOR 信号，而没有激活 SREBP-1c。总之，PKD1 突变在器官水平上发挥了适应性功能，而没有增加转化风险。
