DDR1 Drives Collagen Remodeling and Immune Exclusion - Pan-Cancer Insights and Therapeutic Targeting in Pancreatic Ductal Adenocarcinoma

Sep 23, 2026

Uploaded by McGucket

Discoidin domain receptor 1 (DDR1), a collagen-binding receptor tyrosine kinase, is positioned as a central regulator of extracellular matrix remodeling and immune escape, yet its cross-cancer scope and therapeutic value in immune-resistant disease remain insufficiently defined. A pan-cancer analysis integrates bulk transcriptomic and single-cell datasets with pathway enrichment to map DDR1 expression, genetic alterations, immune infiltration, and clinical outcomes. DDR1 is consistently elevated across 21 cancer types, correlating with poorer prognosis, immune exclusion, and immunosuppressive pathway activation. In pancreatic ductal adenocarcinoma, DDR1-high ductal cells associate with reduced cytotoxic T cell infiltration, expanded regulatory T cell populations, and DDR1 blockade restores CD8+ infiltration and enhances chemotherapy responses in KPC models.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages30

Reading Time1 h 16 min

AccessFree to download

Abstract

Introduction

Article DDR1 Drives Collagen Remodeling and Immune Exclusion: Pan-Cancer Insights and Therapeutic Targeting in Pancreatic Ductal Adenocarcinoma Xuan Huang 1,2, Guangjun Jing 1, Kudelaidi Kuerban 1,3, Jiajun Fan 1, Mei Yu 2, Shanglin Yang 2, Wei Chen 2, Litao Huang 2, Dianwen Ju 1, Yi Zhun Zhu 2 and Li Ye 2, * Academic Editors: David Alexander Forsyth Gillespie and Anna Pryczynicz Received: 1 June 2025 Revised: 25 July 2025 Accepted: 7 August 2025 Published: 10 August 2025 Citation: Huang, X.; Jing, G.; Kuerban, K.; Fan, J.; Yu, M.; Yang, S.; Chen, W.; Huang, L.; Ju, D.; Zhu, Y.Z.; et al. DDR1 Drives Collagen Remodeling and Immune Exclusion: Pan-Cancer Insights and Therapeutic Targeting in Pancreatic Ductal Adenocarcinoma. Int. J. Mol. Sci. 2025, 26, 7731. [https://doi.org/10.3390/](https://doi.org/10.3390/)[ ](https://doi.org/10.3390/)ijms26167731 Copyright: © 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://creativecommons.org/](https://creativecommons.org/)[ ](https://creativecommons.org/)[licenses/by/4.0/](licenses/by/4.0/)) . 1 Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, School of Pharmaceutical Sciences, Fudan University, Shanghai 201100, China; [21111030066@m.fudan.edu.cn](21111030066@m.fudan.edu.cn) (X.H.); [21111030008@m.fudan.edu.cn](21111030008@m.fudan.edu.cn) (G.J.); [kudelaidi@fudan.edu.cn](kudelaidi@fudan.edu.cn) (K.K.); [jiajunfan12@fudan.edu.cn](jiajunfan12@fudan.edu.cn) (J.F.); [dianwenju@fudan.edu.cn](dianwenju@fudan.edu.cn) (D.J.) 2 School of Pharmacy & Laboratory of Drug Discovery from Natural Resources and Industrialization, Macau University of Science and Technology, Macau SAR, China; [ymuabelinda@163.com](ymuabelinda@163.com) (M.Y.); [2230028448@student.must.edu.mo](2230028448@student.must.edu.mo) (S.Y.); [3230005606@student.must.edu.mo](3230005606@student.must.edu.mo) (W.C.); [lihuang@must.edu.mo](lihuang@must.edu.mo) (L.H.) 3 School of Life Science and Technologies, Tongji University, Shanghai 200065, China * Correspondence: [lye@must.edu.mo](lye@must.edu.mo) Abstract Discoidin domain receptor 1 (DDR1), a collagen-binding receptor tyrosine kinase, plays a key role in extracellular matrix remodeling, tumor progression, and immune evasion. However, DDR1’s comprehensive role across diverse cancers and its therapeutic potential in immune-resistant tumors remain poorly defined. We performed a pan-cancer analysis integrating bulk transcriptomic datasets, single-cell RNA sequencing, and pathway enrichment to evaluate DDR1 expression, genetic alterations, and its associations with immune cell infiltration and clinical outcomes. DDR1 was consistently overexpressed in 21 cancer types, correlating with poor prognosis and reduced immune cell infiltration. Mechanistically, DDR1 promoted collagen remodeling, immune exclusion, and upregulated immunosuppressive pathways. Single-cell analysis in pancreatic ductal adenocarcinoma (PDAC) revealed DDR1-high ductal cells associated with reduced cytotoxic T cell infiltration and increased regulatory T cell populations. Therapeutic blockade of DDR1 in an immunocompetent KPC mouse model of PDAC disrupted collagen architecture, enhanced CD8+ T cell infiltration, and improved responses to chemotherapy, highlighting a direct link between DDR1 inhibition and immune reactivation. These findings establish DDR1 asa key mediator of collagen-driven immune resistance and a promising therapeutic target for overcoming immune exclusion, especially in PDAC and other collagen-rich solid tumors. Keywords: discoidin domain receptor 1; extracellular matrix; pan-cancer analyses; immune infiltration; pancreatic ductal adenocarcinoma 1. Introduction Discoidin domain receptor 1 (DDR1) is a collagen-binding receptor tyrosine kinase (RTK) that preserves extracel

FAQs

What role does DDR1 play in tumor progression and immune escape?

DDR1 is a collagen-binding receptor tyrosine kinase that regulates extracellular matrix remodeling, promoting tumor progression and facilitating immune evasion through immunosuppressive signaling.

How was DDR1 evaluated across cancers in this study?

DDR1 expression, genetic alterations, and associations with immune infiltration and clinical outcomes were assessed using integrated pan-cancer analyses combining bulk transcriptomic datasets and single-cell RNA sequencing with pathway enrichment.

What is the reported immune impact of DDR1 inhibition in pancreatic ductal adenocarcinoma?

Therapeutic DDR1 blockade disrupts collagen architecture, increases CD8+ T cell infiltration, and improves chemotherapy responses in an immunocompetent KPC mouse model, supporting immune reactivation.

Sep 23, 2026

Uploaded by McGucket