The type I collagen paradox in PDAC progression: microenvironmental protector turned tumor accomplice

Type I collagen (Collagen I, Col I), a principal component of the tumor extracellular matrix (ECM) that accounts for 80% of total ECM collagen, has emerged as a crucial factor in tumor biology. Recent research has found that Col I has influenced tumor growth, invasion, migration, and prognosis by forming a physical barrier and interacting with components in the tumor microenvironment (TME). Pancreatic ductal adenocarcinoma (PDAC) is characterized by a prominent stromal microenvironment with remarkable cellular and spatial heterogeneity, which significantly impacts the biology of the disease and its resistance to treatment. As research on the influence of ECM on tumor behavior progresses, the role of Col I in tumor occurrence and development has also been gradually expounded. Unlike the pro-tumorigenic role caused by excessive deposition in other cancers, PDAC features a dense stroma with spatial heterogeneity, where Col I deposition exhibits paradoxical pro- and anti-tumor effects: Cancer-associated fibroblasts secrete heterotrimeric Col I (α1/α1/α2), which initially suppresses tumor growth by recruiting M1 macrophages, while tumor cells produce homotrimeric Col I (α1/α1/α1, 2-3% of total Col I) to promote immune evasion via CXCL5 secretion and CD8⁺ T cell reduction. Mechanistically, Col I activates TGF-β/SMAD3 signaling to drive epithelial-mesenchymal transition (EMT) and enhances matrix stiffness, increasing tumor cell migration by 60-80% in 3D cell culture models. Thus, understanding the complex interactions between Col I and other microenvironmental components may enhance its anti-tumor action while suppressing its pro-tumor activity, potentially improving PDAC patients' survival. In this review, we discuss the current research progress regarding the function of Col I in PDAC tumors and summarize its contributions to PDAC progression, thus providing a basis for follow-up research and potential targets for cancer treatment.