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

Li, J.; Macchia, J.; Elhossiny, A. M.; Arya, N.; Kadiyala, P.; Branch, G. L.; Peterson, N.; Liu, J.; Kwon, R.; Machicado, J. D.; Wamsteker, E.-J.; Schulman, A.; Philips, G.; Menees, S.; Singhi, A. D.; Sahai, V.; Fang, J. M.; Frankel, T. L.; Bednar, F.; Pasca di Magliano, M.; Shi, J.; Carpenter, E. S.

doi:10.1101/2025.03.18.643943

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bioRxiv · 10.1101/2025.03.18.643943

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

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Abstract

Background & AimsIntraductal 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. MethodsTo 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. ResultsWe 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 ST dataset containing a larger number of IPMN samples including non-tumor bearing IPMN (i.e. low-grade IPMN in isolation). Immunofluorescence staining of a large cohort of patient tissues confirmed the presence of KRT17-positive cells, which were found to comprise a small subset of epithelial cells within histologically low-grade IPMN in a patchy distribution. ConclusionsOur 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. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=115 SRC="FIGDIR/small/643943v2_ufig1.gif" ALT="Figure 1000"> View larger version (43K): org.highwire.dtl.DTLVardef@47d380org.highwire.dtl.DTLVardef@18e7ab2org.highwire.dtl.DTLVardef@1193ffeorg.highwire.dtl.DTLVardef@b84a98_HPS_FORMAT_FIGEXP M_FIG Graphical Abstract C_FIG

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Li, J., Macchia, J., Elhossiny, A. M., Arya, N., Kadiyala, P., Branch, G. L., Peterson, N., Liu, J., Kwon, R., Machicado, J. D., Wamsteker, E.-J., Schulman, A., Philips, G., Menees, S., Singhi, A. D., Sahai, V., Fang, J. M., Frankel, T. L., Bednar, F., Pasca di Magliano, M., Shi, J., Carpenter, E. S.. 2025-03-19. Spatial analysis of IPMNs defines a paradoxical KRT17-positive, low-grade epithelial population harboring malignant features. https://doi.org/10.1101/2025.03.18.643943

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