Therapy-induced senescence in normal tissue promotes breast cancer metastasis

Disseminated tumour cells, particularly in ER+ breast cancers, typically exhibit a period of dormancy that renders them insensitive to targeting by chemotherapy. Additionally, chemotherapy treatment can result in normal tissue damage, including the induction of cellular senescence. Using mouse and human breast cancer models, we demonstrate that systemic chemotherapy administration results in accumulation of long-lived senescent stromal fibroblasts and promotes metastatic outgrowth. Chemotherapy-induced senescent fibroblasts upregulate a senescence associated secretory phenotype (SASP) that accelerates 3D tumour spheroid growth by stimulating mitogenic signalling. Senolytic drugs can effectively eliminate chemotherapy-induced senescent fibroblasts in vitro, but show only modest efficacy in vivo, at least in part due to the upregulation of resistance mechanisms. In conclusion, systemic chemotherapy can establish a productive microenvironment for colonisation and outgrowth of disseminated cancer cells, however, optimisation of senotherapies for effective targeting of senescent fibroblasts is required to establish them as useful additions to standard chemotherapy. ### Competing Interest Statement The authors have declared no competing interest.