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Immature low-density neutrophils exhibit metabolic flexibility that facilitates breast cancer liver metastasis

ABSTRACT: Neutrophils play a key role in the control of metastatic progression. Neutrophils are phenotypically heterogeneous and can exert either anti- or pro-metastatic functions. Here, we demonstrate that tumor cells capable of forming liver metastases induce an accumulation of neutrophils in the peripheral blood and liver parenchyma. Cancer cell-derived G-CSF, in concert with other factors, mobilizes immature low-density neutrophils that promote liver metastasis. In contrast, mature high-density neutrophils inhibit the formation of liver metastases. Transcriptomic and metabolomic analyses of high- and low- density neutrophils reveal engagement of numerous metabolic pathways specifically in low-density neutrophils. Low-density neutrophils exhibit enhanced global bioenergetic capacity, through their ability to engage mitochondrial-dependent ATP production, and remain capable of executing pro-metastatic neutrophil functions, including NETosis, under nutrient-deprived conditions. Together, these data reveal that distinct pro-metastatic neutrophil populations exhibit a high degree of metabolic flexibility, which facilitates metastatic progression and the formation of liver metastases.

ORGANISM(S): Mus musculus

PROVIDER: GSE123669 | GEO | 2019/06/26

REPOSITORIES: GEO

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Project description:Breast cancer cells display preferences for specific metastatic sites including the bone, lung and liver. Metastasis is a complex process that relies, in part, on interactions between disseminated cancer cells and resident/infiltrating stromal cells that constitute the metastatic microenvironment. Distinct immune infiltrates can either impair the metastatic process or conversely, assist in the seeding, colonization and growth of disseminated cancer cells. Using in vivo selection approaches, we previously isolated 4T1-derived breast cancer cells that preferentially metastasize to these organs and tissues. In this study, we examined whether the propensity of breast cancer cells to metastasize to the lung, liver or bone is associated with and dependent on distinct patterns of immune cell infiltration. Immunohistocytochemistry and immunohistofluorescence approaches were used to quantify granulocytic infiltrates within distinct metastases and depletion of Gr1+ cells was performed to functionally interrogate the role of myeloid/granulocytic infiltrates in promoting metastasis to these organs. We show that T lymphocytes (CD3+), myeloid-derived/granulocytic cells (Gr-1+) cells and neutrophils (NE+) exhibit the most pronounced recruitment in lung and liver metastases, with markedly less recruitment within bone metastatic lesions. Interestingly, these infiltrating cell populations display different patterns of localization within soft tissue metastases. T lymphocytes and neutrophils are localized around the periphery of liver metastases whereas they were dispersed throughout the lung metastases. Furthermore, Gr-1+ cell-depletion studies demonstrate that infiltrating myeloid-derived/granulocytic cells, including neutrophils, are essential for the formation of breast cancer liver metastases but dispensable for metastasis to the lung and bone. Finally, we demonstrate that neutrophils that infiltrate and surround the liver metastases are polarized towards an N2 phenotype, which have previously been shown to enhance tumor growth and metastasis. Our results demonstrate that the liver metastatic potential of breast cancer cells is heavily reliant on interactions with infiltrating myeloid/granulocytic cells in the liver microenvironment.

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Immature low-density neutrophils exhibit metabolic flexibility that facilitates breast cancer liver metastasis

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