Intraductal Papillary Mucinous Neoplasm Cellular Plasticity linked with Repeat Element Dysregulation
Authors: Pankaj Amaya , Raabe Michael J. , Song Yuhui , Patel Bidish K. , Xu Katherine , Kocher Joshua R. , Richieri Peter , Caldwell Nicholas J. , Ni Peiyun , Ganci Maria L , Nieman Linda T. , Zhang Mingjuan L. , Mino-Kenudson Mari , Deshpande Vikram , Bardeesy Nabeel , Castillo Carlos Fernandez-Del , Aryee Martin J. , Ting David T. , Hernandez-Barco Yasmin G. 
Published: January 2025

ABSTRACTBackground and aimsIntraductal papillary mucinous neoplasms (IPMNs) are preneoplastic pancreatic lesions that present on a spectrum of histologic phenotypes with 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. This 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.MethodsA total of 63 lesions from 22 patients with resected IPMNs of different histologies and degrees of dysplasia were analyzed with whole transcriptome spatial analysis (GeoMx). Of these, 49 lesions from 18 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 IPMN was enriched for basal-like epithelium and infiltration of Treg cells. Intestinal IPMN was enriched for classical epithelium and macrophage infiltrates. Gastric 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 reveals a phylogeny starting from Gastric IPMN to Intestinal and Pancreaticobiliary branches associated with higher-grade dysplasia and repeat RNA expression.ConclusionSpatial transcriptomics of IPMN identified transcriptional plasticity between gastric, pancreaticobiliary, and intestinal histologies and a molecular continuum between these cell states. Elevated repeat element expression was linked with cells in transition between cell states and identify cellular progression to high-grade dysplasia.WHAT YOU NEED TO KNOWBackground and ContextIntraductal papillary mucinous neoplasms (IPMNs) present with a wide range of morphologies with variable potential to progress to invasive cancer.New FindingsThis study utilized spatial transcriptomic analysis in IPMN that revealed that gastric, pancreaticobiliary, and intestinal morphologies are on a molecular continuum with aberrant repeat RNA expression as a marker of transdifferentiation.LimitationsThis study provides the basis of repeat RNAs as a marker of transdifferentiation in a cohort of 22 patients, which will need validation in a larger study.Clinical Research RelevanceTranscriptional program changes in epithelial and mesenchymal cell states with repeat RNA sequences reflect cellular plasticity that are associated with IPMN progression. Application of RNA phenotype biomarkers for IPMN risk stratification merit further investigation.Basic Research RelevanceSingle-cell transcriptional trajectory analysis reveals IPMN histologies are on a continuum that begins with low-grade gastric morphology with different cell state changes towards a high-grade gastric/pancreaticobiliary or an intestinal phenotype. Understanding the genetic and epigenetic drivers of cell states can uncover potential strategies to intercept IPMN progression to cancer.Lay summaryWe have used spatial transcriptomic technology to create a high-resolution map of intraductal papillary mucinous neoplasms (IPMNs), a significant precursor to pancreatic cancer, which revealed distinct cell type composition that can be used to inform risk of developing invasive cancer.