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Updated: Jul 28, 2026
Molecular Profiling of the Invasive Tumor Microenvironment in a 3-Dimensional Model of Colorectal Cancer Cells and Ex vivo Fibroblasts
Published on: April 29, 2014
Multi-Omic and Spatial Profiling Identifies an Epithelial DKK1 Associated with Microenvironmental Remodeling in
Jiajia Xu1,2, Kaiqiang Qian3, Yanyu Ding1,2
1Department of Immunology, School of Basic Medical Sciences, Center for Big Data and Population Health of IHM, Anhui Medical University, Hefei 230032, China.
Abstract:
Objective: 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. Methods: 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. Results: 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. Conclusions: 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.
Insights
Dickkopf-1 (DKK1) is an epithelial regulator driving pancreatic cancer progression and immune changes. Targeting DKK1 may offer new therapeutic strategies for pancreatic ductal adenocarcinoma (PDAC).
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genomics
Background:
- Pancreatic ductal adenocarcinoma (PDAC) is marked by a desmoplastic stroma and immune evasion.
- Identifying key regulators of PDAC progression and its microenvironment is crucial for developing effective treatments.
Purpose of the Study:
- To identify and characterize clinically relevant regulators of PDAC.
- To understand the role of these regulators in malignant progression and tumor microenvironment reprogramming.
Main Methods:
- Integrated multi-cohort transcriptomic data (bulk, single-cell, spatial).
- Validated findings using machine learning and independent cohorts.
- Assessed DKK1 expression, spatial distribution, and functional impact via knockdown assays.
Main Results:
- Identified DKK1, COL10A1, SULF1, and SLC24A3 as key regulators.
- DKK1, expressed by tumor cells, correlates with malignant progression and intratumoral heterogeneity.
- DKK1 influences epithelial-endothelial and endothelial-immune signaling, myeloid infiltration, and cytotoxic lymphocyte levels.
- DKK1 knockdown impairs PDAC cell migration, proliferation, and clonogenicity, increasing apoptosis.
Conclusions:
- DKK1 is an epithelial-derived regulator implicated in PDAC progression and tumor microenvironment remodeling.
- DKK1 shows potential as a biomarker and therapeutic target for PDAC.
- DKK1-targeted therapies could be combined with stroma-modulating agents and immunotherapy.
