CDH2 marks a fibroblast-associated stromal cell state in pancreatic ductal adenocarcinoma.

Cadherin-2 (CDH2) has been implicated in angiogenesis-related tumor biology, but its microenvironmental significance remains unclear. To clarify the role of CDH2 in a biologically informative setting, we used a two-round site-selection strategy and identified pancreatic ductal adenocarcinoma (PDAC) as the final study context. Integrative single-cell, spatial, and regulatory analyses were then performed to define the cellular localization and biological meaning of CDH2 in the PDAC microenvironment. CDH2 was reproducibly localized to a fibroblast-associated stromal compartment rather than to a broadly endothelial compartment. Within fibroblasts, CDH2-positive cells were enriched for extracellular matrix remodeling, mesenchymal activation, wound-healing, angiogenesis-related, and TGF-beta-associated programs, supporting a coherent stromal remodeling state. Additional cancer-associated fibroblast (CAF) subtype signature analysis indicated that this state preferentially overlapped with a myofibroblastic CAF-like (myCAF-like)/extracellular matrix-remodeling CAF-like program rather than a dominant inflammatory or antigen-presenting CAF-like program. Communication analysis further showed that CDH2-positive fibroblasts occupied a primarily inter-compartmental, sender-dominant, extracellular matrix-centered signaling niche characterized by prominent collagen-, fibronectin-, and laminin-related interactions with stromal, malignant, myeloid, and endothelial-associated compartments. Spatial transcriptomic mapping supported tissue-level concordance between the CDH2-associated fibroblast state and an extracellular matrix-centered stromal program. Regulatory and counterfactual attenuation analyses further implicated candidate upstream regulators, including RUNX2, SMAD3, and TCF21. Together, these findings indicate that, in PDAC, CDH2 marks a fibroblast-associated CAF-like stromal cell state linked to extracellular matrix remodeling rather than to a directly vascular-centered program.