Epithelial memory of inflammation limits tissue damage while promoting pancreatic tumorigenesis

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.

Automated summary

Inflammation plays a key role in promoting pancreatic ductal adenocarcinoma (PDAC), especially in the presence of KRAS mutations. Researchers have found that a transient inflammatory event can prime pancreatic epithelial cells for subsequent transformation by oncogenic KRAS, even long after the inflammation has resolved. This adaptation allows for the reactivation of acinar-to-ductal metaplasia (ADM) in response to recurring inflammatory events, potentially offering a protective mechanism against tissue damage.