作者
Edoardo Del Poggetto,Ing-Kang Ho,Chiara Balestrieri,Er-Yen Yen,Shaojun Zhang,Francesca Citron,Rutvi Shah,Denise Corti,Giuseppe R. Diaferia,Chieh-Yuan Li,Sara Loponte,Federica Carbone,Yoku Hayakawa,G. Valenti,Shan Jiang,Luigi Sapio,Hong Jiang,Prasenjit Dey,Sisi Gao,Angela K. Deem,Stefan Rose–John,Wantong Yao,Haoqiang Ying,Andrew D. Rhim,Giannicola Genovese,Timothy P. Heffernan,Anirban Maitra,Yichen Wang,Linghua Wang,Giulio Draetta,Alessandro Carugo,Gioacchino Natoli,Andrea Viale
摘要
Inflammation is a major risk factor for pancreatic ductal adenocarcinoma (PDAC). When occurring in the context of pancreatitis, KRAS mutations accelerate tumor development in mouse models. We report that long after its complete resolution, a transient inflammatory event primes pancreatic epithelial cells to subsequent transformation by oncogenic KRAS. Upon recovery from acute inflammation, pancreatic epithelial cells display an enduring adaptive response associated with sustained transcriptional and epigenetic reprogramming. Such adaptation enables the reactivation of acinar-to-ductal metaplasia (ADM) upon subsequent inflammatory events, thereby limiting tissue damage through a rapid decrease of zymogen production. We propose that because activating mutations of KRAS maintain an irreversible ADM, they may be beneficial and under strong positive selection in the context of recurrent pancreatitis.