Targeting a novel secreted protein to modulate MMP activity and restrain lung adenocarcinoma metastasis

Metastasis remains one of the major causes of mortality in lung adenocarcinoma, whereas effective therapies to prevent tumor dissemination remain limited. In our study, we identified complement 1q and tumor necrosis factor-related protein 7 (C1QTNF7), a poorly characterized and dysregulated protein in lung adenocarcinoma, as a potential regulator of metastatic progression. Across six independent proteomic cohorts, we observed a consistent downregulation of C1QTNF7 in tumor tissues compared with paired normal tissues adjacent to the tumor (NAT). Lung adenocarcinoma patients with higher C1QTNF7 expression exhibited earlier-stage disease, better pathological differentiation, and prolonged survival, suggesting that C1QTNF7 may exert a biological function beyond serving as a prognostic marker. Transcriptomic profiling revealed that C1QTNF7-low tumors were enriched for metastasis-related signatures. In contrast, overexpression of C1QTNF7 in cell models significantly suppressed these pathways. Functional assays validated that C1QTNF7 suppressed cell migration and invasion in vitro , and further restrained metastatic growth in mouse orthotopic models. Subsequent analysis revealed that matrix metalloproteinases (MMPs), including MMP1, MMP9, and MMP15, were negatively regulated by C1QTNF7 at both the expression and activity levels. Notably, this suppression was consistent across clinical samples and cell models, suggesting that these MMPs may act as key downstream effectors modulating the anti-invasive function of C1QTNF7. Treatment with conditioned medium or recombinant C1QTNF7 protein recapitulated the anti-invasive effects, indicating an extracellular, receptor-mediated mechanism. Furthermore, experiments using the truncated mutant protein demonstrated that the C1q globular domain primarily mediates this activity. Together, our findings unveil C1QTNF7 as a novel secreted protein with potent anti-metastatic activity in lung adenocarcinoma. By suppressing MMP-driven invasion, C1QTNF7 contributes to a favorable clinical outcome. Given its secretory nature and functional domain specificity, C1QTNF7 represents a promising therapeutic candidate for targeting tumor metastasis in lung adenocarcinoma.