Neutrophils support lung colonization of metastasis-initiating breast cancer cells Stefanie K. Wculek and Ilaria Malanchi identified neutrophils as the main component and driver of metastatic establishment within the pre-metastatic lung microenvironment in mouse breast cancer models. Neutrophils play a fundamental role in inflammatory responses and their contribution to tumourigenesis is still controversial. Using various strategies to block neutrophil recruitment to the pre-metastatic site, they demonstrated that neutrophils specifically support metastatic initiation. Importantly, they found that neutrophil-derived leukotrienes aid the colonization of distant tissue by selectively expanding the sub-pool of cancer cells that retain high tumorigenic potential. Genetic or pharmacologic inhibition of the leukotriene-generating enzyme arachidonate 5-lipoxygenase (Alox5) abrogates neutrophil pro-metastatic activity and consequently reduces metastasis. Their results reveal the efficacy of using targeted therapy against a specific tumour microenvironment component and indicate that neutrophil Alox5 inhibition may limit metastatic progression. In the presence of a growing tumour, subclinical changes in the leukocyte composition at distant sites have been reported to favour metastatic growth. Cancer cells within a tumour are heterogeneous and retain different tumorigenic potentials. Nonetheless, metastasis-initiating cells (MICs) depend on a favourable microenvironment to efficiently grow at the distant site. They reasoned that an altered presence of leukocytes within distant tissue of tumour-bearing hosts might influence specific subsets of disseminating cancer cells. They investigated this hypothesis using the lung metastatic MMTV-polyoma middle T antigen (PyMT) mammary tumour mouse model, which allows monitoring of the cell sub-population functionally-defined by a higher metastasis initiation ability (CD24+ CD90+ MICs). In accordance with previous reports, they found CD11b+ Ly6G+ neutrophils to be systemically mobilised in MMTV-PyMT tumour-bearing mice and, despite their low frequency within the primary tumour microenvironment, they were the main immune component that increased in metastatic lungs. Importantly, CD11b+ Ly6G+ cells accumulated in the lung before cancer cells infiltrated the tissue (pre-metastatic lung) and their numbers increased during metastatic progression (metastatic lung). They addressed the functional relevance of high CD11b+ Ly6G+ neutrophil numbers by analysing metastatic progression of MMTV-PyMT tumour-bearing mice in a neutropenic granulocyte colony-stimulating factor (Gcsf) null background. Mice deficient in G-CSF expression developing mammary tumours failed to accumulate neutrophils in the lungs. Notably, genetic neutropenia resulted in a robust reduction of spontaneous lung metastNeutrophils support lung colonization of metastasis-initiating breast cancer cells Stefanie K. Wculek and Ilaria Malanchi identified neutrophils as the main component and driver of metastatic establishment within the pre-metastatic lung microenvironment in mouse breast cancer models. Neutrophils play a fundamental role in inflammatory responses and their contribution to tumourigenesis is still controversial. Using various strategies to block neutrophil recruitment to the pre-metastatic site, they demonstrated that neutrophils specifically support metastatic initiation. Importantly, they found that neutrophil-derived leukotrienes aid the colonization of distant tissue by selectively expanding the sub-pool of cancer cells that retain high tumorigenic potential. Genetic or pharmacologic inhibition of the leukotriene-generating enzyme arachidonate 5-lipoxygenase (Alox5) abrogates neutrophil pro-metastatic activity and consequently reduces metastasis. Their results reveal the efficacy of using targeted therapy against a specific tumour microenvironment component and indicate that neutrophil Alox5 inhibition may limit metastatic progression. In the presence of a growing tumour, subclinical changes in the leukocyte composition at distant sites have been reported to favour metastatic growth. Cancer cells within a tumour are heterogeneous and retain different tumorigenic potentials. Nonetheless, metastasis-initiating cells (MICs) depend on a favourable microenvironment to efficiently grow at the distant site. They reasoned that an altered presence of leukocytes within distant tissue of tumour-bearing hosts might influence specific subsets of disseminating cancer cells. They investigated this hypothesis using the lung metastatic MMTV-polyoma middle T antigen (PyMT) mammary tumour mouse model, which allows monitoring of the cell sub-population functionally-defined by a higher metastasis initiation ability (CD24+ CD90+ MICs). In accordance with previous reports, they found CD11b+ Ly6G+ neutrophils to be systemically mobilised in MMTV-PyMT tumour-bearing mice and, despite their low frequency within the primary tumour microenvironment, they were the main immune component that increased in metastatic lungs. Importantly, CD11b+ Ly6G+ cells accumulated in the lung before cancer cells infiltrated the tissue (pre-metastatic lung) and their numbers increased during metastatic progression (metastatic lung). They addressed the functional relevance of high CD11b+ Ly6G+ neutrophil numbers by analysing metastatic progression of MMTV-PyMT tumour-bearing mice in a neutropenic granulocyte colony-stimulating factor (Gcsf) null background. Mice deficient in G-CSF expression developing mammary tumours failed to accumulate neutrophils in the lungs. Notably, genetic neutropenia resulted in a robust reduction of spontaneous lung metast