Abstract A080: Spatial transcriptomic analysis reveals obesity driven upregulation of inflammatory markers and matrix remodeling in healthy donor pancreas

Abstract

Pancreatic Ductal Adenocarcinoma (PDAC) is a lethal disease with a 5-year survival rate of 13%. This low survival rate is due in part to insufficient knowledge surrounding pre-cancerous lesions and lack of early detection methods, leading to late-stage diagnoses and inadequate treatment options. Understanding the mechanisms that lead to pre-cancerous lesion progression and tumor development is crucial to developing tools for early detection and interception. The most common precursor lesions for PDAC are pancreatic intraepithelial neoplasias (PanINs), which are classified into low-grade or high-grade (carcinoma in situ). Low-grade PanINs are prevalent in the general population; however, the majority of these never progress to high-grade lesions or cancer. While some well-characterized mutations such as those in KRAS have been identified to contribute to low grade PanIN formation, the cell-intrinsic and -extrinsic factors that drive progression to high-grade status in human tissues have not been identified. Several lifestyle factors are known to increase risk of tumor formation: smoking, alcohol, dietary/exercise habits, and obesity. However, the molecular changes prompted by these factors to drive early progression have not been fully studied. One of the main challenges in understanding them is the lack of access to human tissues that model normal and early-stage disease without the presence of adenocarcinoma. A unique opportunity to overcome this difficulty is access to transplant donors, where the pancreas is not allocated to a recipient and can be used for research. We have collected 25 pancreata that reflect distinct lifestyles factors and focused our initial studies on BMI/obesity. From each donor pancreas, we collected FFPE samples from at least three spatially distinct areas and selected regions of interest for spatial transcriptomics analysis. Using this data, we performed differential gene expression on tissues containing PanINs from high or low BMI donors and analyzed them using pathway enrichment analysis to understand how obesity affects lesion progression and the surrounding tissue. Preliminary analysis revealed enrichment in high BMI samples in extracellular matrix remodeling, proliferation, and pro-inflammatory signaling pathways, all of which suggest advancement toward a diseased state. Ongoing analysis will continue to assess cell composition, spatial organization, and differential pathway usage in the distinct cell types across these tissues. Future analyses will compare these results to PanINs from low and high BMI patients with diagnosed PDAC and use primary cell cultures to model progression. In summary, studying pancreata from healthy human populations allows for a deeper understanding of the molecular factors that lead to lesion progression and early tumor formation, particularly from those with lifestyle factors that increase risk for PDAC such as obesity. Understanding these mechanisms will allow for the identification of future diagnostic early detection markers as well as early interception targets.