增强的细胞因子信号传导和铁死亡防御相互作用引发肥胖相关的胰腺导管腺癌。
Enhanced cytokine signaling and ferroptosis defense interplay initiates obesity-associated pancreatic ductal adenocarcinoma.
发表日期：2024 Aug 08
作者：
Rexiati Ruze, Yuan Chen, Jianlu Song, Ruiyuan Xu, Xinpeng Yin, Qiang Xu, Chengcheng Wang, Yupei Zhao
来源：
CANCER LETTERS
摘要：
肥胖是包括胰腺癌（PC）在内的多种癌症的重要危险因素，但其潜在机制仍不清楚。在我们的研究中，使用来自不同代谢状态的人类受试者的血清培养胰腺导管上皮细胞，揭示肥胖患者的血清改变炎症细胞因子信号传导和铁死亡，其中白细胞介素34（IL-34）表达和铁死亡防御之间的相互增强在这些细胞中观察到。值得注意的是，致癌性 KRASG12D 放大了它们的相互作用，这导致饮食诱导的肥胖小鼠通过巨噬细胞介导的免疫抑制引发胰腺导管腺癌 (PDAC)。人类样本的单细胞 RNA 测序 (scRNA-seq) 显示，细胞因子信号传导、铁死亡防御和免疫抑制与 PDAC 进展期间患者的体重指数 (BMI) 相关。我们的研究结果提供了肥胖、炎症、铁死亡防御和胰腺癌之间的机制联系，为预防和治疗肥胖相关 PDAC 提出了新的治疗靶点。版权所有 © 2024。由 Elsevier B.V. 出版。
Obesity is a significant risk factor for various cancers, including pancreatic cancer (PC), but the underlying mechanisms are still unclear. In our study, pancreatic ductal epithelial cells were cultured using serum from human subjects with diverse metabolic statuses, revealing that serum from patients with obesity alters inflammatory cytokine signaling and ferroptosis, where a mutual enhancement between interleukin 34 (IL-34) expression and ferroptosis defense was observed in these cells. Notably, oncogenic KRASG12D amplified their interaction and this leads to the initiation of pancreatic ductal adenocarcinoma (PDAC) in diet-induced obese mice via macrophage-mediated immunosuppression. Single-cell RNA sequencing (scRNA-seq) of human samples showed that cytokine signaling, ferroptosis defense, and immunosuppression are correlated with the patients' body mass index (BMI) during PDAC progression. Our findings provide a mechanistic link between obesity, inflammation, ferroptosis defense, and pancreatic cancer, suggesting novel therapeutic targets for the prevention and treatment of obesity-associated PDAC.Copyright © 2024. Published by Elsevier B.V.