Decoding collagen cues: the interplay of integrins and discoidin domain receptors in health and disease

Sep 29, 2026

The extracellular matrix (ECM) provides biochemical and biophysical cues that govern cell behavior in health and disease. Collagens are abundant and structurally essential, producing tissue-specific ECM signatures. Integrins and discoidin domain receptors (DDRs) act as primary collagen sensors, but they bind through distinct mechanisms and generate different signaling kinetics. This review clarifies crosstalk between integrin β1 and DDRs, emphasizing DDR2. It details cooperative, compensatory, or antagonistic signaling shaped by tissue specificity, development, and pathology, with consequences for adhesion, migration, and ECM remodeling. The DDR–integrin axis is key in fibrosis and cancer, affecting fibroblast activation, drug resistance, metastasis, and immune suppression, and supports therapeutic targeting to overcome ECM-driven resistance.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages18

Reading Time45 min

AccessFree to download

Abstract

Introduction

Collagens and ECM structure

Trono et al. Journal of Biomedical Science (2026) 33:8 [https://doi.org/10.1186/s12929-025-01211-0](https://doi.org/10.1186/s12929-025-01211-0) REVIEW Open Access Decoding collagen cues: the interplay of integrins and discoidin domain receptors in health and disease Paola Trono1*, Ilenia Masi2, Flavia Ottavi2 and Laura Rosanò2* Abstract The extracellular matrix (ECM) provides critical biochemical and biophysical cues that regulate cell behavior in health and disease. Collagens dominate in abundance and structural importance, shaping tissue-specific ECM signatures that guide cellular behavior. Two major and distinct transmembrane receptor families, integrins and discoidindomain receptors (DDRs), serve as primary sensors for collagens, yet they employ fundamentally distinct binding mechanisms and signaling kinetics. While both can activate shared downstream pathways, their functional interplay remains complex and context-dependent, with the potential to fine-tune cellular responses to ECM cues. This review deciphers the nuanced crosstalk between integrin β1 and DDRs, with a particular focus on the understudied DDR2, across physiological and pathological processes. We discuss how this interplay, which evolves from cooperative to compensatory or even antagonistic signaling, is influenced by variables, such as tissue specificity, developmental timing, and pathological context, dictating cell adhesion, migration, and ECM remodeling. Key examples include DDRs acting as allosteric regulators to license integrin activation, their partnership in mechanotransduction during development, and their divergent roles in aging tissues, where altered collagen mechanics shift the receptor hierarchy. In pathology, the DDR-integrin axis is pivotal in fibrosis and cancer, influencing fibroblast activation, drug resistance, metastatic outgrowth, and immune suppression within the tumor microenvironment. Notably, the receptors can function both independently and synergistically; for instance, DDR2 in cancer-associated fibroblasts regulatesintegrin-mediated mechanosignaling to promote metastasis, while in other contexts, both receptors activate distinct survival pathways. Understanding the signaling dynamics and mechanisms of these receptors is necessary for deciphering how cells interpret ECM signals and how these mechanisms contribute to disease progression, especially in those diseases marked by collagen remodeling. This comprehension is crucial for developing novel therapeutic strategies. Emerging evidence suggests that combined targeting DDRs and integrins can synergistically overcome ECM-mediated therapy resistance, enhance immune infiltration, and reprogram pathological microenvironments, offering a promising approach for treating fibrosis and collagen-rich cancers. Keywords Discoidin domain receptor (DDR) 1 and 2, Integrins, Cancer, Collagen, Targeted therapies, Aging, Fibrosis, Extracellular matrix (ECM), Tyrosine kinase receptor (TKR) *Correspondence: Paola Trono[paola.trono@cnr.it](paola.trono@cnr.it)[ ](paola.trono@cnr.it)Laura Rosanò [laura. rosano@cnr.it](laura. rosano@cnr.it) © The Author(s) 2026, modified publication 2026. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit [http:

FAQs

How do collagens influence cell behavior in health and disease?

Collagens shape tissue-specific ECM signatures that regulate cellular differentiation, function, and homeostasis. They provide biochemical and biophysical cues that guide cell behavior.

What distinguishes integrins from discoidin domain receptors (DDRs) in collagen sensing?

Integrins and DDRs are both primary collagen sensors, but they use fundamentally different binding mechanisms and signaling kinetics. They can activate shared downstream pathways while producing context-dependent functional outcomes.

Why is the DDR–integrin axis important in fibrosis and cancer?

The review highlights that the DDR-integrin axis drives key pathological processes in fibrosis and cancer. It influences fibroblast activation, therapy resistance, metastatic progression, and immune suppression within the tumor microenvironment.

Sep 29, 2026

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