Chemotherapy awakens dormant cancer cells in lung by inducing neutrophil extracellular traps
Menée à l'aide de lignées cellulaires, de modèles murins ainsi que d'échantillons tumoraux et d'échantillons sanguins issus de patientes atteintes d'un cancer du sein, cette étude met en évidence un mécanisme par lequel la chimiothérapie, en induisant la sénescence des fibroblastes et la formation de pièges extracellulaires à neutrophiles, favorise la prolifération des cellules tumorales dormantes disséminées via le remodelage de la matrice extracellulaire
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.
Cancer Cell , résumé, 2025