Spatial Transcriptome Profiling of Intraductal Papillary Mucinous Neoplasms Establishes a Molecular Framework for Risk Stratification

A minority of patients with intraductal papillary mucinous neoplasm (IPMN) will develop pancreatic ductal adenocarcinoma (PDAC) while the majority harbor indolent disease. Histopathologic examination of resected specimens has demonstrated multiple sub-types including pancreaticobiliary (PB), intestinal (INT), and gastric foveolar (GF) that may harbor either low-grade (LGD) or high-grade dysplasia (HGD). Studies have suggested that PB epithelium and HGD confer an elevated risk of malignancy relative to other entities, however given the significant heterogeneity of subtype and grade within an individual patient, bulk tissue analyses have not clarified the gene expression programs corresponding to high-risk and low-risk disease. Here, we establish the transcriptomic framework of high-risk IPMN by leveraging digital spatial profiling of ductal epithelial regions (n = 83 after quality control) derived from surgically resected IPMN tissues (n = 12 patients) encompassing the spectrum of histologic subtypes (24 PB, 38 INT, 21 GF) and grades of dysplasia (36 LGD, 47 HGD). Globally, PB and GF expression patterns diverged from INT, suggesting two progenitor lineages. Transcriptional dysregulation within PB lesions mirrored that of conventional PDAC, whereas GF foci appeared indolent, and INT lesions constituted a proliferative phenotype that did not resemble PDAC. Biological processes implicated in neoplastic progression included inflammatory signaling and cell proliferation, which occurred with relative prominence in PB and INT subtypes, respectively. Taken together, the genes associated with high-risk IPMN nominated by this study may facilitate the development of an accurate molecular risk stratification assay for IPMN. One Sentence Summary Spatial profiling of the ductal epithelial subtypes and grades of dysplasia found within IPMN yields new markers of high-risk disease and insights into malignant progression.