Digital Spatial Profiling of Intraductal Papillary Mucinous Neoplasms: Towards a Molecular Framework for Risk Stratification

Abstract

The histopathologic heterogeneity of intraductal papillary mucinous neoplasms (IPMN) complicates the prediction of pancreatic ductal adenocarcinoma (PDAC) risk. Intratumoral regions of pancreaticobiliary (PB), intestinal (INT), and gastric foveolar (GF) epithelium may occur with either low-grade dysplasia (LGD) or high-grade dysplasia (HGD). We used digital spatial RNA profiling of dysplastic epithelium (83 regions) from surgically resected IPMN tissues (12 patients) to differentiate subtypes and predict genes associated with malignancy. The expression patterns of PB and GF lesions diverged from INT, suggesting that PB and GF arise from a common lineage. Transcriptional dysregulation within PB lesions mirrored that of PDAC, whereas INT and GF foci did not. Tumor necrosis factor/nuclear factor {kappa}B (TNF-NF{kappa}B) and cell cycle (cycling-S, cycling-G2/M) programs occurred with relative prominence in PB and INT subtypes, respectively. Taken together, this study delineates markers of high-risk IPMN and insights into malignant progression. One Sentence SummarySpatial profiling of the intratumoral heterogeneity of IPMN yields markers of high-risk disease and insights into malignant progression.