EPITHELIAL MEMORY OF RESOLVED INFLAMMATION LIMITS TISSUE DAMAGE WHILE PROMOTING PANCREATIC TUMORIGENESIS
Author ORCID Identifier
Date of Graduation
Doctor of Philosophy (PhD)
Giulio F. Draetta
Inflammation is a major risk factor for pancreatic ductal adenocarcinoma. When occurring in the context of pancreatitis, mutations of KRAS accelerate tumor development. We discovered 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, epithelial cells of the pancreas display an enduring adaptive response associated with sustained transcriptional and epigenetic reprogramming. Such adaptation enables the prompt reactivation of acinar-to-ductal metaplasia (ADM) upon subsequent inflammatory events, thus efficiently limiting tissue damage via rapid decrease of zymogen production. We propose that since activating mutations of KRAS maintain an irreversible ADM, they may be beneficial and under strong positive selection in the context of recurrent pancreatitis.
Inflammation, epithelial memory, ADM, Kras mutation, PDAC
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