Locally producing antibacterial peptide to deplete intratumoral pathogen for preventing metastatic breast cancer
Shizhen Geng, T. Xiang, Yaru Shi, Mengnian Cao, Danyu Wang, Jing Wang, Xinling Li, Haiwei Song, Zhenzhong Zhang, Jinjin Shi, Junjie Liu, Airong Li, Sun Ke
Abstract
Metastatic dissemination is the major cause of death from breast-cancer (BC). Fusobacterium nucleatum ( F.n ) is widely enriched in BC and has recently been identified as one of the high-risk factors for promoting BC metastasis. Here, with an experimental model, we demonstrated that intratumoral F.n induced BC aggressiveness by transcriptionally activating Epithelial-mesenchymal transition-associated genes. Therefore, the F.n may be a potential target to prevent metastasis. Given the fact that cancer-associated fibroblasts (CAFs) are abundant in BC and located near blood vessels, we report an optogenetic system that drives CAF to in situ produce human antibacterial peptide LL37, with the characteristics of biosafety and freely intercellular trafficking, for depleting intratumoral F.n , leading to a 72.1% reduction in lung metastatic nodules number without affecting the balance of the systemic flora. Notably, mild photothermal treatment was found that could normalize CAF, contributing to synergistically inhibiting BC metastasis. In addition, the system can also simultaneously encode a gene of TNF-related apoptosis-inducing ligand to suppress the primary tumor. Together, our study highlights the potential of local elimination of tumor pathogenic bacteria to prevent BC metastasis. An optogenetic system (OBA/pHSP-LL37) targeting cancer-associated fibroblasts (CAF) was designed to in situ deplete intratumoral pathogen for preventing metastatic breast-cancer.