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

Available for download on Tuesday, December 28, 2021

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