Spatial Analysis of Intraductal Papillary Mucinous Neoplasms Defines a Paradoxical Keratin 17-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). Although 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 vs 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 KRT17, S100A10, and CEACAM5, markers that are enriched in PDAC. We validated this high-risk gene signature in both single-cell RNA sequenced samples and an external spatial transcriptomic dataset containing a larger number of IPMN samples with non-tumor bearing IPMN (ie, low-grade IPMN in isolation). Immunofluorescence staining of a large cohort of patient tissues confirmed the presence of Keratin 17-positive cells, which were found to comprise a small subset of epithelial cells within histologically low-grade IPMN in a patchy distribution.

CONCLUSIONS

Our study demonstrates that Keratin 17 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.