Therapy-induced senescence in normal tissue promotes breast cancer metastasis

Abstract

Disseminated tumour cells frequently exhibit a period of dormancy that renders them insensitive to targeting by chemotherapeutic agents, conversely the systemic delivery of chemotherapies can result in normal tissue damage. Using multiple mouse and human breast cancer models, we demonstrate that prior chemotherapy administration enhances metastatic colonisation and outgrowth. In vitro, chemotherapy treatment induces fibroblast senescence associated with a senescence associated secretory phenotype (SASP) that accelerates 3D tumour spheroid growth. These chemotherapy-treated fibroblasts, and their pro-tumourigenic function, can be effectively eliminated by targeting the anti-apoptotic protein BCL-xL. In vivo, chemotherapy treatment induces SASP expression in normal tissues, however the accumulation of senescent cells is limited and BCL-xL inhibitors are unable to reduce chemotherapy-enhanced metastasis. This likely reflects that chemotherapy-exposed normal tissues support metastatic colonisation via the secretion of pro-tumourigenic factors and remodelling of the extracellular matrix, but that damaged stromal cells do not enter a full BCL-xL-dependent senescence or switch their dependency to other anti-apoptotic BCL-2 family members. In summary, this study highlights the role of the metastatic microenvironment in controlling outgrowth of disseminated tumour cells and the need to identify novel therapeutic approaches to effectively limit the pro-tumourigenic effects of chemotherapy-induced normal tissue damage.