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Identification of a novel stress-neutrophil-cancer axis promoting lung metastasis in breast cancer

ABSTRACT: Mental stress is widely recognized as a significant risk factor for breast cancer, exerting detrimental effects on both progression and prognosis. Its specific role in regulating breast cancer metastasis remains explorable. Herein, we prepared chronic stress models with MMTV-PyMT-derived spontaneous mammary tumor mice and GFP-4T1-transplanted metastatic breast cancer mice, followed by examinations of lung metastasis and single-cell sequencing analysis of the pre-metastatic lung microenvironment. Upon chronic stress stimulation, we observed a notable increase in tumor growth and lung metastasis, which was accompanied by the induction of a novel subtype of neutrophils, designated as cancer-stress primed neutrophils (Neu_CSP), characterized by the overexpression of Ccl3, Ccl4, Cxcl2, Il1r2, and C/ebpβ. Pseudotime trajectory analysis demonstrated that chronic stress caused a shift of neutrophils from the cancer primed neutrophils (Neu_CP) subtype to the Neu_CSP subtype in the lung. The glucocorticoid receptor NR3C1 mediated the stress hormone corticosterone (CORT)-induced expression of C/ebpβ in neutrophils, which thereafter promoted the expression of Ccl3 and Ccl4 at the transcriptional level. The differentiation of neutrophils into the Neu_CSP subtype promoted the lung metastasis of Ccr1+ breast cancer cells via chemotactic interactions between Ccl3/Ccl4 in neutrophils and Ccr1 in cancer cells. We used anti-Ly6G antibody to deplete neutrophils, or applied an optimized CRISPR/Cas9 approach for conditional knockout of Ccl3/Ccl4 in neutrophils, or used BX471 to inhibit CCR1 in breast cancer cells, all significantly reduced lung metastases in breast cancer both in vitro and in vivo. This study not only demonstrates a novel stress-neutrophil-cancer axis promoting lung metastasis in breast cancer, but also provides potential strategies for preventing or reducing lung metastasis by targeting the Neu_CSP subtype of neutrophils or CCR1(+) breast cancer cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE297920 | GEO | 2025/05/27

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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Identification of a novel stress-neutrophil-cancer axis promoting lung metastasis in breast cancer

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