肥胖与胰腺癌的风险有关。然而，肥胖促进胰腺癌发生的机制仍不清楚。我们研究了肥胖对Pdx1-Cre; LSL-KrasG12D+/-（KC）小鼠胰腺癌发生的影响。我们用二甲双胍来拯救肥胖和NETs的影响。中性粒细胞外网（NETs）的促肿瘤作用在体内和体外进一步评估。我们发现肥胖明显促进了小鼠胰腺导管内上皮瘤（mPanIN）的进展。在肥胖小鼠体内，mPanIN导管细胞的增殖率和上皮-间充质转化（EMT）增加。在肥胖小鼠的胰腺中发现更多的脏器内脂肪细胞、PD-L1+ 中性粒细胞浸润和NETs形成，而脏器内脂肪细胞可以招募中性粒细胞并促进NETs 的形成。后者可以通过TLR4依赖途径在体内和体外诱导导管细胞的炎症反应，如IL-1β的上调所示。二甲双胍和DNase I在体内和体外显著逆转了肥胖和NETs的促肿瘤作用。我们的研究提供了肥胖对遗传模型促进胰腺癌发生的因果证据，并揭示了NETs调节mPanIN进展的机制。版权所有 © 2023年Elsevier B.V. 出版。

Obesity has been linked to a higher risk of pancreatic cancer. However, the mechanism by which obesity promote pancreatic carcinogenesis is still unclear. We investigated the effect of obesity on pancreatic carcinogenesis in Pdx1-Cre; LSL-KrasG12D+/- (KC) mice. Metformin was administrated to rescue the effects of obesity and NETs. The pro-tumorigenic effects of neutrophil extracellular traps (NETs) were further evaluated in vivo and vitro. We found that obesity significantly promoted the progression of murine pancreatic ductal intraepithelial neoplasia (mPanIN). The proliferation rate and epithelial-mesenchymal transition (EMT) of mPanIN ductal cells were increased in obese mice. More visceral adipocytes, PD-L1+ neutrophil infiltration and NETs formation were found in the pancreas of obese mice and visceral adipocytes could recruit neutrophils and promote NETs formation. The latter could induce an inflammatory response in ductal cells via TLR4-dependent pathways both in vivo and vitro, as demonstrated by upregulation of IL-1β. Metformin and DNase I significantly reversed the pro-tumorigenic effects of obesity and NETs in vivo and in vitro. Our study provides causal evidence for the contribution of obesity in promoting pancreatic carcinogenesis in genetic model and reveals the mechanism by NETs to regulate mPanIN progression.Copyright © 2023. Published by Elsevier B.V.