Src/FN1 pathway activation drives tumor cell cluster formation and metastasis in lung cancer: A promising therapeutic target.

Lung cancer remains the leading cause of cancer-related death globally, with metastasis driven by circulating tumor cells (CTCs)-particularly clusters-being a major treatment challenge. Despite their critical role, the biological differences between single CTCs and CTC clusters remain unclear. Here, we comprehensively compared their behavioral, transcriptomic, and proteomic profiles in lung cancer models. Compared with single cells, CTC clusters present enhanced metastatic potential, greater survival in the bloodstream and increased resistance to microenvironment. Mechanistically, the Src/FN1 pathway is centrally activated in clusters, promoting intercellular cohesion and protecting against immune clearance and stress in circulation. Pharmacological inhibition of Src with the clinical inhibitor KX2-391 disrupted clustering, impaired CTC survival, and reduced metastasis in preclinical models. Our findings identify the Src/FN1 pathway as a key vulnerability in CTC cluster-driven metastasis, suggesting that Src inhibitors are promising therapeutic strategies to disrupt clustering and improve outcomes in patients with metastatic lung cancer.