He Dasa, Wu Qiuyao, Tian Pu, Liu Yin, Jia Zhenchang, Li Zhenwei, Wang Yuan, Jin Yuchen, Luo Wenqian, Li Ling, Zhang Peiyuan, Jin Qianlu, Zhao Wenjing, Hu Weiguo, Liang Yajun, Zhou Bin, Yang Qifeng, Jiang Yi-Zhou, Shao Zhi-Ming, Hu Guohong
CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
Cancer Cell. 2025 Jun 24. doi: 10.1016/j.ccell.2025.06.007.
Disseminated tumor cells (DTCs) can remain in a non-proliferative, dormant state for years in distant organs, but the exogenous causes triggering their reactivation and metastatic colonization are unclear. Here, we demonstrate that chemotherapeutic drugs, including doxorubicin and cisplatin, enhance proliferation and lung metastasis of dormant breast cancer cells. Using a recombinase-based dormancy tracing system, DormTracer, we confirm chemotherapy-induced reactivation of dormant DTCs leading to metastatic relapse. Mechanistically, chemotherapy induces fibroblast senescence, which promotes formation of neutrophil extracellular traps (NETs) through secreted proteins. NETs promote dormant DTC proliferation through extracellular matrix remodeling. Importantly, combining senolytic drugs, dasatinib and quercetin, with doxorubicin inhibits post-therapy DTC reactivation and suppresses metastatic relapse. This study provides direct evidence of dormancy awakening and reveals a mechanism underlying detrimental effect of chemotherapy on metastasis, highlighting potential strategies to improve cancer treatment.
播散肿瘤细胞（DTCs）可在远处器官中处于非增殖性休眠状态数年，但触发其重新激活和转移定植的外部原因尚不清楚。在此，我们证明包括阿霉素和顺铂在内的化疗药物可增强休眠乳腺癌细胞的增殖和肺转移。使用基于重组酶的休眠追踪系统DormTracer，我们证实化疗诱导休眠DTCs重新激活，导致转移复发。从机制上讲，化疗诱导成纤维细胞衰老，通过分泌蛋白促进中性粒细胞胞外陷阱（NETs）的形成。NETs通过细胞外基质重塑促进休眠DTCs增殖。重要的是，将衰老细胞溶解药物达沙替尼和槲皮素与阿霉素联合使用可抑制治疗后DTCs的重新激活并抑制转移复发。本研究提供了休眠唤醒的直接证据，并揭示了化疗对转移产生有害影响的潜在机制，突出了改善癌症治疗的潜在策略。
