Abstract Background and Aims: Intraductal papillary mucinous neoplasms (IPMNs) are heterogeneous precursor lesions to pancreatic ductal adenocarcinoma (PDAC), characterized by distinct histologic subtypes and variable risk of malignant progression. While the Pancreaticobiliary (PB), Intestinal, and Gastric subtypes are histologically defined, their molecular states and evolutionary trajectories remain poorly understood. Repetitive elements (e. g. , LINE1, HERVs, HSATII) are increasingly recognized as markers of tumor plasticity in cancer. We used high-plex spatial transcriptomics and RNA in situ hybridization (ISH) to dissect epithelial, fibroblast, and immune phenotypes across subtypes, and evaluate repeat RNA expression as a molecular readout of progression. Methods: We profiled 63 lesions from 18 resected IPMN cases using GeoMx whole-transcriptome spatial analysis, including custom probes for LINE1 (ORF1/2), HERVH/K, and HSATII. Regions of interest were segmented into epithelial, fibroblast, and immune compartments, stratified by grade and histologic subtype. A subset of 49 lesions from 18 patients was further profiled using CosMx single-cell spatial imaging using their Universal cell characterization (1k) panel to reconstruct transcriptional trajectories. We validated LINE1 expression using RNA ISH across 217 tissue cores, which included Low-grade, High-grade, and Invasive lesions from 70 IPMN patients. Results: PB-IPMN was enriched for basal-like epithelial programs, Treg infiltration, and myofibroblastic CAFs (myCAFs). Intestinal-IPMN was dominated by classical epithelial states, macrophage infiltration, and balanced CAFs. Gastric-IPMN was heterogeneous, with a near-equal basal/classical epithelial mix, inflammatory (iCAF) enrichment, and diverse immune infiltration. Spatial pseudotime and principal component analysis revealed a molecular continuum between the three histological subtypes, starting from Low-grade Gastric and transitioning to the higher grade Intestinal and PB subtypes. Repeat RNA expression was highest as the grade of the disease progressed, indicating that repeat activation may be associated with cell state changes and not with specific basal or epithelial identity. Importantly, LINE1 RNA ISH in an extended cohort (70 patients, 217 cores) confirmed that LINE1 expression increases with disease severity: from 26. 5% of LGD to 44. 0% in HGD and 56. 2% in Invasive lesions, suggesting that repeat expression may act as an early marker of molecular transition. Conclusion: Spatial multi-compartment profiling of IPMN reveals that progression to invasive disease involves coordinated epithelial, stromal, and immune reprogramming across histological subtypes. Repeat element activation marks high-grade lesions but arises from microenvironmental interactions, particularly in the transitional epithelial cells. Our findings establish a repeat - immune - plasticity axis that may enable early detection of high-risk IPMN and reveal new targets for immunoprevention. Citation Format: Amaya Pankaj, Michael J. Raabe, Yuhui Song, Bidish K. Patel, Katherine Xu, Joshua R. Kocher, Peter Richieri, Nicholas J. Caldwell, Peiyun Ni, Maria L. Ganci, Linda T. Nieman, Mingjuan L. Zhang, Mari Mino-Kenudson, Vikram Deshpande, Nabeel Bardeesy, Carlos Fernandez-Del Castillo, Martin J. Aryee, David T. Ting, Yasmin G. Hernandez-Barco. Intraductal Papillary Mucinous Neoplasm Cellular Plasticity Linked with Repeat Element Dysregulation abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85 (18Suppl₃): Abstract nr B117.
Pankaj et al. (Sun,) studied this question.