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

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.

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.

We identified a subpopulation of histologically low-grade IPMN epithelial cells that express malignant transcriptional features including KRT17 , S100A10 and CEACAM5 , 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.

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.