Graduation Date

Spring 5-10-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Biochemistry & Molecular Biology

First Advisor

Surinder K. Batra

Abstract

Intraductal Papillary Mucinous Neoplasms (IPMNs) are the most common cystic neoplasms of the pancreas and have a significant potential to progress into invasive cancer and pancreatic ductal adenocarcinoma (PDAC). Despite their clinical importance, the molecular mechanisms driving the progression from benign IPMNs to invasive PDAC remain poorly understood. This gap in knowledge limits our ability to develop effective strategies for early detection, targeted therapies, and patient risk stratification. One factor implicated in IPMN progression is mucin overproduction, particularly the overexpression of MUC4, which has been linked to high-grade lesions and poor prognosis. In this study, we investigated the role of MUC4 in IPMN progression using a human MUC4 transgenic mouse model with an oncogenic KrasG12Dbackground, recapitulating key features of human IPMN. Our results demonstrated that MUC4 overexpression accelerates cyst formation, mimicking various human IPMN subtypes, including gastric, pancreatobiliary, and intestinal types. Histological analysis showed increased cellular proliferation and stromal fibrosis, indicating that MUC4 promotes progression toward invasive disease. Global transcriptome analysis further identified the upregulation of immune-related genes and factors within the tumor microenvironment (TME), suggesting that MUC4 plays a pivotal role in modulating the TME and promoting PDAC development from IPMN. Further, our transcriptomic analysis of PDAC lesions identified KLF15 as a key regulator of IPMN development, with its expression significantly elevated in IPMN lesions. Functional studies revealed that KLF15 promotes tumorigenesis by enhancing cell proliferation and colony formation. In vivo inhibition of KLF15 resulted in a marked reduction in tumor growth, underscoring its critical role in IPMN progression. Moreover, we identified the oncogenic GNAS/PKA/CREB signaling axis as a key pathway regulating KLF15 expression in IPMN, suggesting that targeting this pathway could offer a novel therapeutic strategy. Additionally, we explored the therapeutic potential of Delta-tocotrienol (DTT), a vitamin E derivative. DTT demonstrated significant antiproliferative and pro-apoptotic effects in vitro in IPMN-derived cells. In vivo, DTT treatment markedly suppressed tumor growth in IPMN xenograft models by modulating mucin. Our findings shed light on the molecular drivers of IPMN progression, particularly the roles of MUC4 and KLF15, and suggest promising targets for therapeutic intervention to prevent progression to PDAC.

Comments

2025 Copyright, the authors

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