Spatial epigenomics reveals stromal niche-associated regulatory programs across pancreatic neuroendocrine tumor grades

Non-functional pancreatic neuroendocrine tumors (NF-PanNETs) account for the majority of pancreatic neuroendocrine neoplasms and exhibit substantial clinical and biological heterogeneity, yet their epigenetic regulation and spatial architecture remain poorly understood. Here, we present an integrative analysis of NF-PanNETs across multiple tumor grades using single-nucleus advent of transposase-accessible chromatin using sequencing (snATAC-seq) and spatial ATAC-seq. snATAC-seq identified grade-associated chromatin accessibility programs characterized by distinct transcription factor activities, including HNF1A and FOXA2 in low-grade tumors, ETS family factors in intermediate-grade tumors, SNAI-associated regulatory programs in high-grade tumors, and CEBPB- and TOX-associated immune states. Spatial ATAC-seq revealed spatially coordinated tumor-stroma interactions, with stroma-proximal regions enriched for MYC/FOX-associated proliferative programs and distal regions exhibiting SNAI-enriched invasive programs. Together, our study provides a spatially resolved epigenomic atlas of NF-PanNETs across tumor grades, offering a resource for understanding epigenetic heterogeneity and generating hypotheses regarding regulatory programs and tumor-stroma interactions for future functional and clinical investigation.