Abstract A055: Dissecting the role of GLP-1 signaling during PDAC initiation and progression

Abstract

Glucagon-like peptide 1 receptor agonist (GLP-1RA) has shown tremendous benefit in treating type 2 diabetes (T2D) and obesity, which include improved glycemic control and substantial weight loss. It has been reported that GLP-1RA is associated with significantly reduced risk of 10 out of 13 obesity-associated cancer including pancreatic cancer in a recent study of over 1.6 million T2D patients. Despite the rapidly growing clinical use of these agonists, the role of GLP-1 signaling during pancreatic cancer initiation and progression remains poorly understood. We aim to understand the role of GLP-1 signaling in pancreatic ductal adenocarcinoma (PDAC) development through the analysis of genetically engineered mouse models (GEMMs). These models have refined our understanding of the cellular origin of PDAC, by showing that both acinar and ductal cells can give rise to PDAC. Acinar cells can initiate PDAC through acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN), leading to invasive carcinoma, whereas ductal cells can generate PDAC through a different trajectory independent from classic PanIN. Importantly, our previous work based on adult acinar and ductal cell-derived GEMMs showed that the cell of origin also influences the molecular subtype of PDAC, as acinar cell-derived tumors express genes associated with the human PDAC classical subtype transcriptional program and ductal cell-derived tumors express genes associated with the human PDAC basal-like subtype transcriptional program. We are leveraging our lineage-specific adult GEMMs to investigate the relationship between GLP-1 signaling and pancreatic tumorigenesis. To start, we have sought to systematically map GLP-1R expression across normal pancreas and different stages of PDAC development in both the acinar and ductal cell derived models. We have assessed GLP-1R expression both at the protein level through immunostaining and at the mRNA level through analysis of bulk and single-cell RNA sequencing datasets, and we will present these data. We have also characterized GLP-1R expression in a host of PDAC cell lines. In parallel, we are establishing complementary Glp1r knock-out mouse models to define the functional contribution of GLP-1R signaling during pancreatic cancer progression, using both conditional knockout and full-body knockout strategies. Together, this work in GEMMs will reveal the role of GLP-1 signaling in PDAC development, providing an understanding of how GLP-1 based therapies might affect tumorigenesis in humans.