Spatial multi-omics resolve epithelium-fibroblast gradients and highlight NESTIN-NOTCH1-expressing subepithelial fibroblasts during human pancreatic tumorigenesis

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ABSTRACT Intraductal papillary mucinous neoplasms (IPMNs) are cystic precursors of pancreatic ductal adenocarcinoma undergoing dynamic epithelial and stromal remodeling during progression. In this study, we integrated computational pathology, cyclic immunofluorescence, and Xenium spatial transcriptomics to define the spatial organization of the IPMN microenvironment. We queried cell-based histopathological features and identified stromal patterns strongly associated with epithelium proximity. Cyclic immunofluorescence and Xenium revealed a subepithelial gradient extending from myofibroblasts to inflammatory fibroblasts. Xenium further identified a distinct subepithelial NOTCH1 - NESTIN -expressing fibroblast subset in myofibroblasts that expands with tumor progression. By recapitulating the spatial remodeling event using human pancreatic tumor cells and primary myofibroblast co-culture models, we demonstrated the capacity of pancreatic tumor cells to induce a NESTIN-expressing state in neighboring myofibroblasts. These findings reveal new dynamic epithelial-stromal interactions through subepithelial NESTIN+ fibroblasts associated with pancreatic tumorigenesis and immediate microenvironment remodeling by active tumor cells, highlighting the power of computational pathology integrated with spatial transcriptomics. STATEMENT OF SIGNIFICANCE By integrating computational pathology, cyclic immunofluorescence, and Xenium spatial transcriptomics, we show that epithelium proximity drives fibroblast identity in IPMNs. We reveal the existence of subepithelial NESTIN-expressing fibroblasts associated with disease progression, and the capacity of human pancreatic tumor cells to remodel myofibroblasts in close contact into NESTIN-expressing fibroblasts.

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