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bioRxiv · 10.1101/2025.01.14.632658

Intraductal Papillary Mucinous Neoplasm Cellular Plasticity linked with Repeat Element Dysregulation

Pankaj, A.·Raabe, M. J.·Song, Y.·Patel, B. K.·Xu, K.·Kocher, J. R.·Richieri, P.·Caldwell, N. J.·Ni, P.·Ganci, M. L.·Nieman, L. T.·Zhang, M. L.·Mino-Kenudson, M.·Deshpande, V.·Bardeesy, N.·Fernandez Del-Castillo, C.·Aryee, M. J.·Ting, D. T.·Hernandez-Barco, Y. G.
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Abstract

BackgroundIntraductal papillary mucinous neoplasms (IPMNs) are preinvasive pancreatic lesions with a spectrum of histologic phenotypes and variable risk in progressing to invasive cancer. Aberrant repetitive element expression has been shown to be functionally linked to cell state changes in pancreatic cancer. ObjectiveThis study utilized spatial transcriptomics with customized repeat element probes to better understand the relationship of histologic subtypes, repeat element dysregulation, and molecular profiles of different cell populations in IPMN. DesignA total of 52 lesions from 18 patients with resected IPMNs of different histologies and degrees of dysplasia were analyzed with whole transcriptome spatial analysis (GeoMx). Of these, 50 lesions from 17 patients were also processed for single-cell spatial molecular imaging (CosMx). Repeat element probes for LINE1, HSATII, HERVK, and HERVH were used for GeoMx and CosMx. ResultsPancreaticobiliary-type IPMN was enriched for basal-like epithelium and infiltration of Treg cells. Intestinal-type IPMN was enriched for classical epithelium and macrophage infiltrates. Gastric-type IPMN was found to have equal basal-like and classical epithelium with a diverse immune infiltrate. Repeat RNAs were expressed at high levels across IPMN phenotypes and enriched in high-grade dysplasia. Single-cell transcriptional trajectory analysis revealed a phylogeny starting from gastric toward intestinal and pancreaticobiliary branches associated with higher-grade dysplasia and repeat RNA expression. ConclusionSpatial transcriptomics of IPMN identified a molecular continuum between histological subtypes supporting a common gastric-type origin that transitions to intestinal and pancreatobiliary phenotypes. This cell state plasticity is linked with repeat element expression that can be a potential biomarker for IPMN progression. What is already known on this topicO_LIMolecular characterization of IPMN subtypes using regional spatial transcriptomics has described the differences between histologies C_LIO_LIRepeat element expression is associated with cell state changes in pancreatic ductal neoplasm C_LI What this study addsO_LISingle cell spatial molecular imaging of IPMN subtypes reveals a cellular and molecular continuum starting from gastric histology with distinct branches to Intestinal and pancreatobiliary subtypes C_LIO_LIRepeat element expression is associated with higher grade IPMN histology C_LIO_LIRepeat element expression is elevated in the histologic and molecular continuum from gastric to intestinal and pancreatobiliary-type IPMN C_LI How this study might affect research, practice, or policyO_LIThese results support a common gastric histology origin of IPMN subtypes with different molecular trajectories towards higher grade disease C_LIO_LIOur findings suggest that repeat RNA expression can be used in conjunction with other transcriptional markers of cell state as a biomarker for IPMN progression C_LI

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Pankaj, A., Raabe, M. J., Song, Y., Patel, B. K., Xu, K., Kocher, J. R., Richieri, P., Caldwell, N. J., Ni, P., Ganci, M. L., Nieman, L. T., Zhang, M. L., Mino-Kenudson, M., Deshpande, V., Bardeesy, N., Fernandez Del-Castillo, C., Aryee, M. J., Ting, D. T., Hernandez-Barco, Y. G.. 2025-01-19. Intraductal Papillary Mucinous Neoplasm Cellular Plasticity linked with Repeat Element Dysregulation. https://doi.org/10.1101/2025.01.14.632658

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