Spatial analysis of IPMNs defines a paradoxical KRT17-positive, low-grade epithelial population harboring malignant features.

Background & Aims: Intraductal papillary mucinous neoplasms (IPMNs) are pancreatic cysts that represent one of the few radiologically identifiable precursors to pancreatic ductal adenocarcinoma (PDAC).Though the IPMN-bearing patient population represents a unique opportunity for early detection and interception, current guidelines provide insufficient accuracy in determining which patients should undergo resection versus surveillance, resulting in a sizable fraction of resected IPMNs only harboring low-grade dysplasia, suggesting that there may be overtreatment of this clinical entity.

Methods: To investigate the transcriptional changes that occur during IPMN progression, we performed spatial transcriptomics using the Nanostring GeoMx on patient samples containing the entire spectrum of IPMN disease including low-grade dysplasia, high-grade dysplasia, and IPMN-derived carcinoma. Single cell RNA sequencing was performed on side branch and main duct IPMN biospecimens.

Results: We identified a subpopulation of histologically low-grade IPMN epithelial cells that express malignant transcriptional features including , and , markers that are enriched in PDAC. We validated and refined this high-risk gene signature by integrating our ST analysis with an external ST dataset containing a larger number of IPMN samples including non-tumor bearing IPMN (i.e. low-grade IPMN in isolation). We confirmed the presence of the KRT17+ population using immunofluorescence on a large cohort of patient tissues, revealing a widespread but patchy distribution of KRT17+ cells in histologically low-grade IPMN.

Conclusions: Our study demonstrates that KRT17 marks a distinct transcriptional signature in a subpopulation of epithelial cells within histologically low-grade IPMN. This population of cells likely represents a transitional state of histologically low-grade epithelial cells undergoing progression to a higher grade of dysplasia and thus may represent a higher risk of progression to carcinoma.