Abstract 636: Role of Apobec3a in pancreatitis and inflammation triggered carcinogenesis
Authors: Woermann Sonja Maria , Thege Fredrik , Valenciana Laura , Cowan Robert , Maitra Anirban 
Published: June 2023

Abstract
Background: Despite great efforts over the last decades, the complex pathogenesis of acute (AP) and chronic pancreatitis (CP), involving the interplay of environmental, metabolic, and genetic factors and how CP eventually progresses to pancreatic cancer, remains incompletely understood. While mutated Kras, an important oncogenic driver in PDAC, has been found mutated in about 40% of CP patients, other mutations or mutagenic drivers potentially arising during the course of this chronic inflammatory disease are not well established. Recently, inflammation-triggered APOBEC single-strand DNA-specific cytidine deaminases were identified as important mutagenic drivers in PDAC. In addition, we unraveled a so far unrecognized role for A3A in driving chromosomal instability (CIN) independent of its deaminase function. Importantly, we found APOBEC3A (A3A), a member of the APOBEC family, to be associated with an IFNg immune response, activated during CP, and in a mouse model of AP, A3A significantly aggravated the course of the disease. These findings led us to conclude that A3A may be an important player in the inflammatory disease of the pancreas, AP and CP, and could act as a mutagenic driver fueling cancer evolution.
Methods: Utilizing our novel genetically engineered mouse models (GEMMs) of conditional humanized wildtype and E72A mutant A3A expression, cerulein-induced AP and CP models, and human CP specimens, as well as a variety of molecular biology assays and sequencing approaches, we aim to elucidate the role of deaminase-competent and deaminase-deficient (mutant) A3A during AP and CP and early carcinogenesis and its implications on inflammation-triggered mutagenesis.
Results: Interestingly, we found that deaminase-competent but not mutant A3A aggravates the severity (edema, necrosis, apoptosis, serum lipase) and inflammatory response during AP and CP. We found an increased inflammatory response in the pancreas as well as in the lungs by performing RNAseq, qPCR, MPO assays, and multiplex immunostainings. In addition, by analyzing human CP specimens, we were able to show that expression of A3A correlates with fibrosis, formation of pre-cancerous lesions, and the severity of the disease. Targeted DNA sequencing revealed a higher rate of mutations in important tumor suppressor/oncogenes when A3A was highly expressed, suggesting that A3A may facilitate inflammation-triggered mutagenesis in a pre-oncogenic setting.
Conclusions: A3A significantly impacts the severity and inflammatory response of AP and CP and may facilitate inflammation-triggered carcinogenesis.
Citation Format: Sonja Maria Woermann, Fredrik Thege, Laura Valenciana, Robert Cowan, Anirban Maitra. Role of Apobec3a in pancreatitis and inflammation triggered carcinogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 636.