Abstract

The poorly characterised contribution of host responses during metastatic progression represents a limitation to target the non-cancer cell component of the tumour. Here we identify neutrophils as the main component and driver of initial metastatic colonisation within pre-metastatic lung microenvironment in breast cancer models. Using various strategies to block neutrophil recruitment to the metastatic tissue, we demonstrate their functional relevance in supporting the more metastatic sub-pool of cancer cells (mCSCs). Importantly, we found leukotrienes as the main paracrine neutrophil-derived mediators within the metastatic niche. Specific genetic or pharmacologic inhibition of the leukotriene-generating enzyme Alox5 abrogates neutrophil pro-metastatic activity and consequently reduces metastasis. Collectively, our results reveal the efficacy of using therapeutic strategies targeting a specific component of the tumour microenvironment and propose neutrophil-derived leukotrienes as a potential therapeutic target to halt metastatic progression.