Beyond the tumour: circulating extracellular matrix fragments as next-generation cancer biomarkers.
Abstract
Tumour progression fundamentally disrupts extracellular matrix (ECM) homeostasis, generating circulating molecular signatures that reflect the integrated activities of cancer cells, stromal fibroblasts and infiltrating immune populations. These tumour ECM-derived fragments comprise specific protease-generated neo-epitopes of collagens, proteoglycans and glycoproteins, and provide dynamic, real-time readouts of microenvironmental remodelling that distinguish them from other classes of biomarker, such as genomic biomarkers. Recent technical advances in neo-epitope detection platforms have enabled measurement of specific ECM fragments with exceptional sensitivity and specificity, transforming these signatures from research tools into clinically viable biomarkers. ECM fragment fingerprints are demonstrating utility across the cancer continuum, including tracking disease activity; differentiating malignancy from benign conditions during early detection; stratifying patients by biological aggressiveness of the disease independent of anatomical staging; monitoring the treatment response with pharmacodynamic precision; and predicting immunotherapeutic efficacy through immune-ECM interaction signatures. Established regulatory pathways through the US Food and Drug Administration Biomarker Qualification Program and European Union In Vitro Diagnostic Regulation frameworks provide clear routes to clinical implementation. Thus, the convergence of robust analytical platforms, mechanistic understanding and regulatory readiness is positioning ECM fragment fingerprinting as a potential emerging component of precision oncology, complementing genomic profiling to enable comprehensive tumour ecosystem characterization and rational therapy selection.
