Endocrine-Exocrine Signaling Drives Obesity-Associated Pancreatic Ductal Adenocarcinoma
Endocrine-Exocrine Signaling Drives Obesity-Associated Pancreatic Ductal Adenocarcinoma
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DOI：
10.1016/j.cell.2020.03.062
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发表时间：
2020-05-14
期刊：
影响因子：
64.5
通讯作者：
Muzumdar, Mandar Deepak
中科院分区：
文献类型：
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作者：
Chung, Katherine Minjee;Singh, Jaffarguriqbal;Muzumdar, Mandar Deepak
肥胖是胰腺导管腺癌（PDAC）的主要可改变危险因素，但肥胖如何以及何时促进PDAC进展尚不清楚。利用原生小鼠模型，我们证明了肥胖在PDAC早期进展中的因果和可逆作用，表明肥胖显着促进肿瘤发生，而遗传或饮食诱导体重减轻可阻断癌症发展。人类和小鼠样本的分子分析确定了肥胖的微环境后果，这些微环境后果促进了肿瘤的发生，而不是新的驱动基因突变，包括在肥胖相关肿瘤中显著的胰岛细胞适应。具体来说，我们确定了肥胖反应中肽激素胆囊收缩素（Cck）的异常β细胞表达，并表明胰岛Cck促进致癌的kras驱动的胰腺导管肿瘤发生。我们的研究认为，PDAC的进展是由肿瘤微环境中与肥胖相关的局部变化驱动的，并且在PDAC的发展中涉及胰岛素以外的内分泌-外分泌信号。
Obesity is a major modifiable risk factor for pancreatic ductal adenocarcinoma (PDAC), yet how and when obesity contributes to PDAC progression is not well understood. Leveraging an autochthonous mouse model, we demonstrate a causal and reversible role for obesity in early PDAC progression, showing that obesity markedly enhances tumorigenesis, while genetic or dietary induction of weight loss intercepts cancer development. Molecular analyses of human and murine samples define microenvironmental consequences of obesity that foster tumorigenesis rather than new driver gene mutations, including significant pancreatic islet cell adaptation in obesity-associated tumors. Specifically, we identify aberrant beta cell expression of the peptide hormone cholecystokinin (Cck) in response to obesity and show that islet Cck promotes oncogenic Kras-driven pancreatic ductal tumorigenesis. Our studies argue that PDAC progression is driven by local obesity-associated changes in the tumor microenvironment and implicate endocrine-exocrine signaling beyond insulin in PDAC development.