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Tumor-associated neutrophil precursors impair homologous DNA repair and promote sensitivity to PARP-inhibition [RNA-seq]

ABSTRACT: Tumor evolution is one of the major mechanisms responsible for acquiring therapy-resistant and more aggressive cancer clones. Whether the tumor microenvironment through immune-mediated mechanisms might promote the development of more aggressive cancer types is crucial for the identification of additional therapeutical opportunities. Here, we identified a novel subset of tumor-associated neutrophils, defined as tumor-associated neutrophil precursors (PreNeu). These PreNeu are enriched in female highly proliferative hormone-dependent breast cancers and impair DNA repair capacity.  Mechanistically, succinate secreted by tumor-associated PreNeu inhibit homologous recombination, promoting error-prone DNA repair through non-homologous end-joining regulated by PARP-1. Consequently, breast cancer cells acquire genomic instability promoting tumor editing and progression. Selective inhibition of these pathways induces increased tumor cell killing in vitro and in vivo. Tumor-associated PreNeu score correlates with copy number alterations in highly proliferative hormone-dependent tumors from breast cancer patients. Treatment with PARP-1 inhibitors counteract the pro-tumoral effect of these neutrophils.

ORGANISM(S): Homo sapiens

PROVIDER: GSE288569 | GEO | 2025/03/18

REPOSITORIES: GEO

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Project description: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.

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Tumor-associated neutrophil precursors impair homologous DNA repair and promote sensitivity to PARP-inhibition [RNA-seq]

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