Multi-Omic and Spatial Profiling Identifies an Epithelial DKK1 Associated with Microenvironmental Remodeling in Pancreatic Ductal Adenocarcinoma

<b>Objective:</b> This study aimed to identify clinically relevant regulators of pancreatic ductal adenocarcinoma (PDAC), a disease characterized by stromal remodeling and immune suppression, and to define their links to malignant progression and microenvironmental reprogramming. <b>Methods:</b> We integrated multi-cohort bulk, single-cell, and spatial transcriptomic datasets and subsequently validated bulk differential expression and network analyses with machine learning-based prioritization in an independent combined cohort (TCGA-PAAD plus GSE62452). Single-cell mapping was used to assess cell-type specificity, positioning candidates along inferCNV- and pseudotime-defined malignant continua. In Visium sections, a DKK1-associated program score quantified intratumoral spatial heterogeneity and informed our analyses of ligand-receptor communication. Bulk immune deconvolution linked gene levels to immune infiltration patterns, and functional assays were used to test the impact of DKK1 knockdown on migration, proliferation, clonogenic growth, and apoptosis in PDAC cells. <b>Results:</b> Four reproducible tumor-associated genes-DKK1, COL10A1, SULF1, and SLC24A3-were prioritized and validated externally. DKK1 was predominantly expressed by epithelial tumor cells and tracked along a malignant progression continuum. Spatially, the DKK1 program localized to epithelial-dominant regions, revealed pronounced intratumoral heterogeneity, and highlighted epithelial-endothelial and endothelial-immune signaling in high-score areas. Immune deconvolution associated higher DKK1 expression with increased myeloid infiltration and reduced cytotoxic lymphocyte signatures. Functionally, DKK1 knockdown impaired migration, proliferation, and clonogenicity while increasing apoptosis. <b>Conclusions:</b> We demonstrate that DKK1 is an epithelial-derived regulator linked to malignant progression and tumor-stroma-immune remodeling, supporting its potential as a biomarker and therapeutic target in PDAC treatment, including rational combinations with stroma-modulating strategies and immunotherapy.