PO.PR02.01 · 预防研究
胰岛激素胆囊收缩素的失调驱动肥胖相关性胰腺癌
Dysregulation of the islet hormone cholecystokinin drives obesity-associated pancreatic cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
胰腺导管腺癌（PDAC）是美国癌症死亡的第三大原因，5 年生存率约为 13%。肥胖是 PDAC 的一个关键危险因素，与发病率增加和生存率降低相关，但肥胖促进 PDAC 发生和进展的机制仍不清楚。为研究肥胖如何驱动 PDAC，我们实验室开发了一种新型的肥胖相关性 PDAC 基因工程小鼠模型，发现与瘦对照组相比，肥胖小鼠的疾病负荷显著增加，而早期诱导的减重可消除这一表型。对肥胖小鼠胰腺的分子分析显示，由于应激反应性 JNK/cJun 信号，内分泌胰腺 beta 细胞中肽激素胆囊收缩素（CCK）显著上调。CCK 在传统上促进外分泌腺泡细胞（推测的 PDAC 起源细胞）释放消化酶，并在胰岛素需求增加（如肥胖）的情况下作为内分泌 beta 细胞的存活因子发挥作用。外源性 CCK 刺激腺泡细胞增殖和导管化生，这是 PDAC 发生的早期必需步骤。引人注目的是，我们发现 beta 细胞 CCK 过表达足以增强瘦小鼠的外分泌肿瘤发生，表型上模拟了肥胖的效应，并验证了 beta 细胞 CCK 作为 PDAC 发生的独立驱动因素。相反，胰腺特异性 CCK 敲除显著消除了肥胖小鼠的外分泌肿瘤发生，使其达到与瘦小鼠相似的水平。关键的是，肿瘤负荷与胰腺 CCK 表达显著正相关，与内源性胰岛素产生负相关，提示是 CCK 而非胰岛素驱动了肥胖相关性肿瘤发生。最后，用 GLP-1 受体激动剂（GLP-1RAs）治疗肥胖小鼠——其可增强葡萄糖刺激的胰岛素分泌并改善 beta 细胞健康——增强了 beta 细胞功能并显著降低了胰腺 CCK 表达。总之，这项工作确立了内分泌-外分泌 CCK（而非胰岛素）作为肥胖驱动 PDAC 的一个此前未被重视的关键介质，并促成了包括 GLP-1RAs 在内的新型转化方法的鉴定，以拦截肥胖相关性 PDAC 的发生。
查看英文原文 English abstract
Pancreatic ductal adenocarcinoma (PDAC) is the third-leading cause of cancer death in the United States with a 5-year survival rate of ~13%. Obesity is a key PDAC risk factor associated with increased incidence and decreased survival, but the mechanisms by which obesity promotes PDAC development and progression remain unclear. To study how obesity drives PDAC, our lab developed a novel genetically engineered mouse model of obesity-associated PDAC and found that obese mice had significantly increased disease burden relative to lean controls, a phenotype which was abrogated by early induced weight loss. Molecular analyses of the pancreata from obese mice showed marked upregulation of the peptide hormone cholecystokinin (CCK) in beta cells of the endocrine pancreas due to stress-responsive JNK/cJun signaling. CCK canonically promotes digestive enzyme release in exocrine acinar cells, the putative PDAC cell-of-origin, and acts as a survival factor in endocrine beta cells under conditions of increased insulin demand, such as obesity. Exogenous CCK stimulates acinar cell proliferation and ductal metaplasia, early prerequisite steps in PDAC development. Strikingly, we found that beta cell CCK overexpression was sufficient to enhance exocrine tumorigenesis in lean mice, phenocopying the effects of obesity and validating beta cell CCK as an independent driver of PDAC development. Conversely, pancreas-specific CCK knockout significantly abrogated exocrine tumorigenesis in obese mice similar to levels seen in lean mice. Critically, tumor burden was significantly positively associated with pancreatic CCK expression and negatively correlated with endogenous insulin production, suggesting that CCK, rather than insulin, drives obesity-associated tumorigenesis. Finally, treatment of obese mice with GLP-1 receptor agonists (GLP-1RAs), which augment glucose-stimulated insulin secretion and improve beta cell health, enhanced beta cell function and significantly decreased pancreatic CCK expression. Together, this work has established endocrine-exocrine CCK - rather than insulin - as a critical previously unappreciated mediator of obesity-driven PDAC and enabled the identification of novel translational approaches, including GLP-1RAs, to intercept obesity-associated PDAC development.
利益披露 Disclosure
D. C. McQuaid, None..
C. C. Garcia, None..
A. Venkat, None..
C. F. Ruiz, None..
C. Zheng, None.