Author ORCID Identifier

https://orcid.org/0000-0003-2325-4057

Date of Graduation

12-2022

Document Type

Dissertation (PhD)

Program Affiliation

Cancer Biology

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Florencia McAllister

Committee Member

Menashe Bar-Eli

Committee Member

Anirban Maitra

Committee Member

Pawel Mazur

Committee Member

Han Liang

Abstract

Adenosine deaminase acting on RNA (ADAR) is an RNA-binding protein that deaminates adenosine (A) to inosine (I). A-to-I editing is an important post-transcriptional mechanism to prevent recognition of endogenous RNA by MDA5, a cytosolic RNA sensor. Activation of MDA5 by viral RNA can stimulate the innate immune system. Thus, ADAR-mediated RNA editing is crucial to distinguish “self” from “non-self”. ADAR has an important role in gene regulation as A-to-I editing alters RNA processing affecting both RNA and protein abundance. Given its importance in regulating innate immunity and transcript abundance, aberrations in Adar expression are implicated in developmental deformities and carcinogenesis. The work presented in this thesis explores the yet undefined role of Adar in pancreatic development and tumor biology. Through genetic mouse models, we conclusively show that the primary function of Adar in the pancreas is to prevent aberrant activation of the Mavs-mediated innate immune pathway, thereby maintaining pancreatic homeostasis. Pancreatic cancer has a desmoplastic stroma and most immune checkpoint blockade therapies fail to restrict it. Almost 18% of pancreatic cancer patient tumors have an upregulation of ADAR. We evaluated clinical data sets and performed in vitro and in vivo studies to understand the function of Adar in pancreatic cancer. In all, the work presented here highlights the crucial role of Adar in pancreatic development and cancer.

Keywords

ADAR, RNA editing, pancreatic cancer, pancreatic development, MAVS

Available for download on Friday, November 10, 2023

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