Abstract A090: Quantitative evaluation of changes to healthy pancreatic microanatomy across the human lifespan

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy, with a five-year survival rate near 10%. The rarity of PDAC contrasts the abundance of its primary precursor lesion, pancreatic intraepithelial neoplasia (PanIN). PanIN is known to be common in surgically resected pancreas and to exist even in normal donor tissue. While surgical samples are commonly used to study precancers and their microenvironments, recent work has demonstrated that the molecular features and stromal populations around PanINs from surgical resections differ dramatically from those seen in donors, emphasizing that study of cancer risk in the general population necessitates better understanding of normal pancreatic microanatomy. Further, while it is known that risk of developing PDAC increases with age, it is unknown whether this risk stems from increasing PanIN burden or from molecular changes to the aging pancreas. Here, using quantitative two-dimensional (2D) and three-dimensional (3D) pathology, we systematically evaluated changes in pancreas composition in donor tissue with age. First, we assembled a 3D cohort consisting of 46 grossly normal, surgically resected and 19 organ donor samples. Second, we assembled two large 2D cohorts including pancreatic histology from Gift of Life Michigan (∼120 donors), which allowed us to map composition across the pancreatic head, body, and tail, and from the GTEx portal (∼300 donors), where paired bulk RNA-sequencing and histology enabled joint morphologic-transcriptomic analysis. We used the CODA pipeline to segment 9 microanatomical components from standard histology images, including PanINs, acinar tissue, collagen, and vasculature. In disease-free donors, PanIN burden was low and increased modestly with age, a pattern reproduced in the independent GTEx cohort. By contrast, surgically resected pancreata carried several-fold higher neoplastic burden, confirming that estimates of PanIN burden derived from surgical resections systematically overstate precancer prevalence in the general population. The Gift of Life organ donor dataset extended the same compositional analysis with added spatial context across the pancreatic head, body, and tail, showing that elevated PanIN burden in some donors is localized to specific pancreatic regions rather than being distributed homogeneously. Pancreas aging was dominated by acinar loss with accumulation of fat and collagen, while PanIN burden rose only slightly, driven by increasingly frequent high PanIN burden outliers in older donors. CODA-guided deconvolution of GTEx bulk RNA-seq identified canonical aging hallmarks in the normal pancreas, including decreased acinar and beta cell function, as well as increased inflammation and senescence. Important future work includes molecular comparison of PanINs from young and old donors to identify drivers of increasing cancer risk with age.