Epithelial Memory of Resolved Inflammation Limits Tissue Damage While Promoting Pancreatic Tumorigenesis

<p>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 <em>via</em> 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.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2021

Authors dc:creator

• Ho, I-Lin
• <p>0000-0002-8914-710X</p>

Contributors dc:contributor

• Giulio F. Draetta
• Andrea Viale
• Dihua Yu

• Inflammation
• epithelial memory
• ADM
• Kras mutation
• PDAC
• Cancer Biology
• Cell Biology
• Disease Modeling
• Medicine and Health Sciences
• Molecular Genetics

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1114

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-2171