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.

中文翻译：

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上皮炎症记忆限制组织损伤，同时促进胰腺肿瘤发生


炎症是胰腺导管腺癌（PDAC）的主要危险因素。当发生胰腺炎时，KRAS 突变会加速小鼠模型中肿瘤的发展。我们报告说，在其完全消退很久之后，短暂的炎症事件会促使胰腺上皮细胞随后被致癌 KRAS 转化。从急性炎症中恢复后，胰腺上皮细胞表现出与持续转录和表观遗传重编程相关的持久适应性反应。这种适应使得腺泡到导管化生（ADM）在随后的炎症事件中能够重新激活，从而通过酶原产生的快速减少来限制组织损伤。我们认为，由于 KRAS 的激活突变维持了不可逆的 ADM，因此它们可能是有益的，并且在复发性胰腺炎的情况下处于强阳性选择的情况下。