Full Project 3 – Pancreatic ADM

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most devastating cancers with poor prognosis and rising incidence. To combat this deadly disease, we should direct our efforts toward preventing PDAC or halting the progression of precursor lesions to invasive disease in parallel to developing novel treatments. One of the earliest known initiating events for PDAC is the process of acinar-to-ductal metaplasia (ADM). Understanding and reduction of ADM formation may reduce early PDAC development and progression. In our previous studies, we used normal pancreatic acinar tissues from donors to study the progression of acinar-to-ductal metaplasia (ADM) and found differences in the extent of ADM. In this competitive renewal, we will expand on and extend our previous study by including diseased tissues from chronic pancreatitis (CP) with PDAC tissues since accumulating evidence suggest that CP is a major precursor to the development of PDAC. We will investigate the progression of cellular and molecular events regulating the interplay between ADM and the microenvironment. Guided by our published and unpublished results, we hypothesize that the differences seen in PDAC are related to differences in how the pancreas microenvironment develops during ADM, which means that ADM and its surrounding microenvironment can be used as a target to treat PDAC. We propose the following specific aims to examine: Aim 1: ADM progression from the healthy pancreas, CP, and PDAC tissues. Aim 2: The roles of pancreatic stellate cells and macrophages in ADM and ADM reversal. Aim 3: Contributions of self-reported patient characteristics to ADM reversal and cell heterogeneity. The proposed studies will impact the field of pancreatic cancer by providing a missing link between differences in outcomes, ADM, tumor microenvironment, and potential treatments for CP and PDAC. The specific focus on the contributions of self-reported patient characteristics on microenvironment remolding during pancreatic metaplasia aligns with the Florida-California Cancer Research, Education and Engagement (CaRE2) Health Center’s overall goal to eliminate differences in cancer health among all people in California, Florida, and across the U.S.