Stress Promotes Lung Metastasis in Breast Cancer by Altering Neutrophil Differentiation

Area of Science:

• Oncology
• Immunology
• Stress Physiology

Background:

• Mental stress is a known risk factor for breast cancer progression and poor prognosis.
• The precise mechanisms by which stress influences breast cancer metastasis remain incompletely understood.

Purpose of the Study:

• To investigate the role of chronic stress in regulating breast cancer metastasis.
• To identify the cellular and molecular mechanisms underlying stress-induced metastasis.

Main Methods:

• Utilized genetically engineered and transplantation mouse models of breast cancer.
• Performed single-cell RNA sequencing on lung premetastatic microenvironments.
• Conducted pseudotime trajectory analysis to track neutrophil differentiation.
• Investigated the role of glucocorticoid receptor (NR3C1) and corticosterone.
• Employed neutrophil depletion (anti-Ly6G), gene knockout (CRISPR/Cas9), and receptor inhibition (BX471) strategies.

Main Results:

• Chronic stress significantly increased breast cancer tumor growth and lung metastasis in mouse models.
• Identified a novel subtype of cancer stress-primed (CSP) neutrophils in the stressed lung microenvironment, overexpressing Ccl3, Ccl4, Cxcl2, Il1r2, and Cebpb.
• Demonstrated that stress shifts neutrophils to the CSP subtype, which promotes lung metastasis of CCR1+ breast cancer cells via CCL3/CCL4-mediated recruitment.
• Showed that targeting neutrophils, Ccl3/Ccl4, or CCR1 significantly reduced breast cancer lung metastasis.

Conclusions:

• Established a stress-neutrophil-cancer axis that drives breast cancer lung metastasis.
• CSP neutrophils, induced by stress via glucocorticoid receptor activation, play a critical role in promoting metastasis.
• Targeting CSP neutrophils or the CCR1 pathway in cancer cells presents promising therapeutic strategies for preventing or treating breast cancer metastasis.