Integrated multiomic atlas of pancreatic solid pseudopapillary neoplasms suggests acinar cells as a potential cell-of-origin

Introduction: Solid pseudopapillary neoplasms (SPNs) of the pancreas are rare, low-grade tumors that typically affect young women and occasionally recur or metastasize. While the histological features and mutational profile of SPNs are well documented, their cell-of-origin and spatial organization remain incompletely understood. The purpose of this study was to delineate the development and spatial transcriptomic landscape of SPNs. Methods: Regions of interest from 10 surgically resected SPN specimens collected between 2020 and 2025 were profiled using the G4X Singular In Situ Multiomic platform. Gene expression data were integrated and analyzed to generate spatial embeddings, followed by unsupervised clustering. Cell types were annotated using canonical markers, and proteomic data were integrated for further resolution. Results: Spatial transcriptomic profiling of 30 SPN sections from 10 patients yielded 3.6 million high-quality cells. The cohort was entirely female, with a median age of 31.5 years. Integrated analysis demonstrated a heterogeneous tumor microenvironment composed of exocrine pancreatic cells, immune cells, fibroblasts, endothelial cells, and tumor cells. Tumor cells demonstrated intra- and inter-tumoral heterogeneity, with five distinct subpopulations: (1) CPB1⁺ tumor cells, (2) MYH11⁺ tumor cells, (3) FN1⁺ VIM⁺ MMP2⁺ tumor cells, (4) IGHG1⁺ FCGR1A⁺ TBX21⁺ tumor cells, and (5) STAT1⁺ TAP1⁺ CD74 + tumor cells. Mapping these tumor transcriptional states back onto the tissue sections revealed distinct microenvironmental niches. IGHG1⁺ FCGR1A⁺ TBX21⁺ tumor cells and MYH11⁺ tumor cells were the most prevalent tumor cells across samples. STAT1⁺ TAP1⁺ CD74 + tumor cells, characterized by elevated antigen-presentation and interferon-signaling programs, were localized in areas with high immune-infiltration, which was further corroborated and delineated proteomically. CPB1⁺ tumor cells showed relatively increased expression of acinar cell markers and formed spatial gradients at tumor-acinar interfaces, suggesting that SPN tumor cells may arise from an acinar lineage. Conclusion: We present the first multiomic analysis of SPNs of the pancreas, establishing a high-resolution atlas of their cellular and spatial architecture. We identify conserved tumor transcriptional and proteomic states that occupy distinct spatial niches. Spatial gradients in CPB1⁺ tumor cells suggest a potential acinar origin for SPN tumor cells, warranting further lineage-focused investigation. These findings collectively refine our understanding of SPN tumor biology.