LOX From Salivary Adenoid Cystic Carcinoma-Associated Fibroblast Promotes Fibrosis in the Pulmonary Pre-metastatic Niche

AIMS: Metastasis is the primary cause of cancer-related mortality. Carcinoma-associated fibroblasts (CAFs) critically promote lung metastasis in salivary adenoid cystic carcinoma (SACC). CAFs within metastatic organs, often termed metastasis-associated fibroblasts (MAFs), drive extracellular matrix (ECM) remodelling during metastasis. Understanding early ECM remodelling events in the metastatic niche may offer crucial insights for inhibiting metastasis. However, the specific mechanisms through which SACC-associated CAFs regulate lung ECM remodelling remain poorly understood. METHODS: CAFs and collagen deposition in murine tissues were visualised using H&E and picrosirius red staining. The role of lysyl oxidase (LOX) in CAF-mediated collagen cross-linking and its underlying molecular mechanisms were examined through western blotting, immunofluorescence staining and collagen contraction assays. RESULTS: In this study, we showed that CAFs enhanced collagen cross-linking, leading to stromal fibrosis during the establishment of the pre-metastatic niche and subsequent SACC lung metastasis. LOX, a copper-dependent enzyme crucial for collagen cross-linking and secreted by CAFs, promotes the activation of lung MAFs and increases their collagen I expression. MAF activation is facilitated by LOX, which induces YAP expression and its nuclear translocation. β-Aminopropionitrile, a specific LOX inhibitor, effectively suppressed fibroblast activation and reduced nuclear YAP expression. CONCLUSIONS: Our findings indicate that soluble LOX secreted by CAFs promotes metastatic progression through the induction of pulmonary fibrosis. Targeting this LOX-mediated pathway may represent a promising therapeutic strategy for preventing lung metastasis in patients with SACC. Furthermore, given the complexity of metastasis, future studies should investigate how fibrosis influences key stages of metastatic colony formation, including the extravasation and dormancy of circulating tumour cells.