Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
MD Anderson UTHealth Graduate School of Biomedical Sciences, Houston, TX 77030, USA.
Science. 2021 Sep 17;373(6561):eabj0486. doi: 10.1126/science.abj0486.
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.
炎症是胰腺导管腺癌（PDAC）的一个主要危险因素。当发生在胰腺炎的背景下时，KRAS 突变会加速小鼠模型中的肿瘤发展。我们报告称，在其完全消退很久之后，短暂的炎症事件会使胰腺上皮细胞对随后的致癌 KRAS 转化做好准备。在急性炎症恢复后，胰腺上皮细胞会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。这种适应使在随后的炎症事件中重新激活腺泡到导管的化生（ADM）成为可能，从而通过快速减少酶原的产生来限制组织损伤。我们提出，因为 KRAS 的激活突变维持了不可逆转的 ADM，因此它们在反复胰腺炎的背景下可能是有益的，并受到强烈的正选择。
