Cancer-Associated Fibrosis: ECM Remodeling and CAF Heterogeneity as Pivotal Drivers and Therapeutic Targets
Background
Cancer-associated fibrosis, driven by dynamic changes in the extracellular matrix (ECM) within the tumor microenvironment (TME), significantly impacts tumor progression, invasion, metastasis, and immune exclusion. Traditional cancer therapies often overlook the critical role of the stroma, leading to suboptimal responses. Understanding the intricate interplay between cancer cells and their surrounding ECM, particularly the contributions of cancer-associated fibroblasts (CAFs), is crucial for developing novel therapeutic strategies that address these stromal barriers and improve patient outcomes.
Study Design
This review synthesizes recent advances in proteomic analyses of insoluble ECM fractions (termed matrisome analysis), along with single-cell RNA sequencing and spatial transcriptomics. The authors investigated how these cutting-edge techniques have revealed cancer-specific patterns of ECM remodeling and dissected the molecular diversity of cancer-associated fibroblasts (CAFs). The focus was on consolidating emerging CAF atlases across various cancers and unraveling the pivotal role of the stroma in shaping tumor biology.
Results
The review highlights that the ECM is a dynamic component of the tumor microenvironment critically involved in cancer progression, invasion, metastasis, immune exclusion, and therapy response. Advanced matrisome analysis and single-cell profiling have identified recurrently upregulated ECM proteins actively contributing to tumor pathology. These include annexin A1, fibrillin-1, fibronectin, periostin, and tenascin-C, all of which promote tumor growth, invasion, angiogenesis, and immune exclusion. The expression of this cancer-associated ECM is largely driven by cancer-associated fibroblasts (CAFs), whose molecular diversity has been extensively characterized. > By investigating the matrisome composition and CAF heterogeneity, these studies have unequivocally unraveled the pivotal role of the stroma in shaping tumor biology and influencing therapeutic responses.
Key Findings
- ECM is a dynamic component of the tumor microenvironment, critically involved in cancer progression, invasion, metastasis, and immune exclusion.
- Advanced
matrisome analysisand single-cell profiling reveal cancer-specific ECM remodeling patterns and CAF heterogeneity. - Upregulated ECM proteins like annexin A1, fibrillin-1, fibronectin, periostin, and tenascin-C drive tumor growth, invasion, and angiogenesis.
- Cancer-associated fibroblasts (CAFs) are primary drivers of cancer-associated ECM expression and are molecularly diverse.
- ECM proteins and CAFs are emerging as crucial biomarkers for patient stratification and novel therapeutic targets.
Why It Matters
This comprehensive review underscores the critical shift towards recognizing the tumor microenvironment (TME), particularly the ECM and CAFs, as central to cancer biology. For clinicians and researchers, this means moving beyond targeting cancer cells alone to developing stroma-directed therapeutic interventions. The identified ECM proteins and CAF subtypes represent promising new biomarkers for patient stratification and novel therapeutic targets. While not a direct protocol, this work provides the mechanistic foundation for future drug development, potentially leading to therapies that disrupt fibrosis, enhance immune infiltration, and improve drug delivery. Clinical translation is still in its early stages, requiring further integration of multi-omics data with clinical outcomes to validate these targets and develop effective treatment strategies.
cancer
tumor microenvironment
extracellular matrix
fibrosis
cancer-associated fibroblasts
biomarkers