Que Zujun, Xi Zhichao, Qi Dan, Dai Rongchen, Li Yang, Liu Mengfan, Luo Bin, Liu Jiajun, Yu Pan, Yang Yun, Wu Erxi, Xu Hongxi, Tian Jianhui
Institute of Oncology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, China.
Institute of Traditional Chinese Medicine Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China.
Sci Adv. 2025 Jul 11;11(28):eadv7377. doi: 10.1126/sciadv.adv7377. Epub 2025 Jul 9.
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.
肺癌仍然是全球癌症相关死亡的主要原因，由循环肿瘤细胞（CTC）——尤其是细胞团簇——驱动的转移是一个主要的治疗挑战。尽管它们起着关键作用，但单个CTC与CTC团簇之间的生物学差异仍不清楚。在这里，我们在肺癌模型中全面比较了它们的行为、转录组和蛋白质组特征。与单个细胞相比，CTC团簇具有更强的转移潜力、在血液中更高的存活率以及对微环境更强的抵抗力。从机制上讲，Src/FN1通路在团簇中被集中激活，促进细胞间黏附，并保护其免受循环中的免疫清除和应激影响。在临床前模型中，使用临床抑制剂KX2-391对Src进行药理学抑制可破坏细胞团簇形成、损害CTC存活并减少转移。我们的研究结果确定Src/FN1通路是CTC团簇驱动转移中的一个关键弱点，这表明Src抑制剂是破坏细胞团簇形成并改善转移性肺癌患者预后的有前景的治疗策略。
