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

Authors

Yongjie Li, Ni Chen, Xin Deng, Liqun Wang

Published in

Human cell. Volume 39. Issue 7. Jul 12, 2026. Epub Jul 12, 2026.

Abstract

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.

PMID:
42437806
Bibliographic data and abstract were imported from PubMed on 13 Jul 2026.

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