Author ORCID Identifier
0000-0002-8914-710X
Date of Graduation
8-2021
Document Type
Dissertation (PhD)
Program Affiliation
Biomedical Sciences
Degree Name
Doctor of Philosophy (PhD)
Advisor/Committee Chair
Giulio F. Draetta
Committee Member
Andrea Viale
Committee Member
Dihua Yu
Committee Member
Anirban Maitra
Committee Member
Haoqiang Ying
Committee Member
Linghua Wang
Abstract
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.
Keywords
Inflammation, epithelial memory, ADM, Kras mutation, PDAC
Included in
Cancer Biology Commons, Cell Biology Commons, Disease Modeling Commons, Molecular Genetics Commons