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Stress Promotes Lung Metastasis in Breast Cancer by Altering Neutrophil Differentiation

ABSTRACT: Mental stress is widely recognized as a significant risk factor for breast cancer, exerting detrimental effects on both progression and prognosis. Herein, we investigated the role of stress in regulating breast cancer metastasis. In genetically engineered and transplantation breast cancer mouse models, chronic stress stimulation increased tumor growth and lung metastasis. Single-cell RNA-sequencing analysis of the pre-metastatic lung microenvironment revealed induction of a previously unrecognized subtype of cancer stress-primed (CSP) neutrophils, characterized by the overexpression of Ccl3, Ccl4, Cxcl2, Il1r2, and Cebpb. Pseudotime trajectory analysis demonstrated that chronic stress caused a shift of neutrophils from the cancer-primed (CP) neutrophil subtype to the CSP subtype in the lung. Activation of the glucocorticoid receptor NR3C1 by the stress hormone corticosterone induced expression of Cebpb in neutrophils, which then promoted transcription of Ccl3 and Ccl4. The differentiation of neutrophils into the CSP subtype promoted lung metastasis of CCR1+ breast cancer cells via CCL3/CCL4-mediated recruitment. Targeting this axis using an anti-Ly6G antibody to deplete neutrophils, a CRISPR/Cas9-mediated approach to conditionally knockout Ccl3/Ccl4 in neutrophils, and BX471 treatment to inhibit CCR1 in cancer cells all significantly reduced breast cancer lung metastasis. Together, this study not only demonstrates a stress-neutrophil-cancer axis that promotes lung metastasis in breast cancer but also provides potential strategies for reducing lung metastasis by targeting CSP neutrophils or CCR1+ breast cancer cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE297920 | GEO | 2025/09/14

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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Stress Promotes Lung Metastasis in Breast Cancer by Altering Neutrophil Differentiation

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