Neutrophils Physically Interact with Tumor Cells to Form a Signaling Niche Promoting Breast Cancer Aggressiveness
Academic Background
Breast cancer is one of the most common malignant tumors among women worldwide, with a complex pathogenesis involving interactions among multiple cell types and signaling pathways. In recent years, the role of the tumor microenvironment (TME) in cancer progression has gradually gained attention. Neutrophils, as an essential component of the immune system, have an incompletely understood function in the tumor microenvironment. Although some studies have shown that neutrophils can promote tumor growth and metastasis in certain contexts, their specific mechanisms in breast cancer remain unclear. Therefore, in-depth research into the interactions between neutrophils and tumor cells is crucial for uncovering the mechanisms of breast cancer progression and developing new therapeutic strategies.
Source of the Paper
This paper was jointly completed by researchers including Sandra Camargo and Ori Moskowitz from Tel Aviv University in Israel, with collaboration from institutions such as the Hubrecht Institute in the Netherlands and the Weizmann Institute of Science. The paper was published in March 2025 in the journal Nature Cancer, titled “Neutrophils physically interact with tumor cells to form a signaling niche promoting breast cancer aggressiveness,” with the DOI 10.1038/s43018-025-00924-3.
Research Process and Results
Research Design
The research team used a transgenic mouse model (MMTV-PyMT) that mimics different stages of human breast cancer, including hyperplasia, early carcinogenesis, advanced carcinogenesis, and metastasis. Through single-cell RNA sequencing (scRNA-seq) and physically interacting cell sequencing (PIC-seq) of mouse mammary tissues at various developmental and carcinogenic stages, the researchers systematically analyzed cellular heterogeneity and intercellular communication in the mammary tissue.
Cell Types and Dynamic Changes
The researchers first conducted comprehensive single-cell sequencing analysis of immune and non-immune cells in mouse mammary tissues, sequencing a total of 16,778 CD45+ immune cells and 12,783 CD45- non-immune cells. Through clustering analysis, they identified multiple immune and non-immune cell types, including monocytes, macrophages, dendritic cells, mast cells, basophils, and neutrophils. In the vascular microenvironment, they also identified endothelial cells, smooth muscle cells, and pericytes.
During mammary development and carcinogenesis, the researchers observed that neutrophils transiently appeared in early developmental stages and re-emerged in advanced carcinogenic stages, physically interacting with tumor cells. Through PIC-seq analysis, they further found that the physical interaction between neutrophils and tumor cells significantly enhanced tumor cell proliferation and invasive properties, as well as endothelial cell proliferation and angiogenesis.
Heterogeneity of Neutrophils
To gain deeper insights into the function of neutrophils in mammary tissue, the researchers performed single-cell sequencing of CD45+Ly6G+ neutrophils and identified seven distinct neutrophil states. These states included cystatin-high neutrophils and young neutrophils associated with early development, as well as MHC-II neutrophils, PTGS2+ neutrophils, and tumor-associated neutrophils (TANs) linked to carcinogenesis. Among these, TANs were significantly enriched in advanced carcinogenic stages and correlated with lower survival rates in breast cancer patients.
Signaling Network Analysis
By integrating PIC-seq and ligand-receptor analysis, the researchers uncovered the signaling network between neutrophils and tumor cells. The study revealed that neutrophils form a complex signaling network with tumor cells and vascular endothelial cells by secreting pro-angiogenic factors such as VEGFA and OSM, promoting tumor proliferation and invasion. Additionally, the research found that tumor-activated macrophages recruit neutrophils into the tumor microenvironment by secreting chemokines like CCL3.
Functional Validation
To validate the function of physical interactions between neutrophils and tumor cells, the researchers conducted in vitro co-culture experiments and scratch assays. The results showed that the physical interaction between neutrophils and tumor cells significantly increased the invasive capacity of tumor cells, while blocking this interaction inhibited tumor cell invasion. Furthermore, through in vivo experiments, the researchers found that neutrophil depletion significantly reduced the proliferative capacity of tumor cells and endothelial cells.
Research Conclusions
This study, through single-cell sequencing and physically interacting cell sequencing, revealed the critical role of neutrophils in breast cancer progression. The research found that the physical interaction between neutrophils and tumor cells promotes tumor proliferation, invasion, and angiogenesis, and is associated with lower survival rates in breast cancer patients. These findings provide new potential targets for breast cancer treatment and highlight the important role of neutrophils in the tumor microenvironment.
Research Highlights
- Innovative Methodology: This study is the first to combine single-cell sequencing with physically interacting cell sequencing, systematically analyzing cellular heterogeneity and intercellular communication in mammary tissue.
- Significant Findings: The research found that the physical interaction between neutrophils and tumor cells significantly promotes tumor proliferation, invasion, and angiogenesis, offering new potential targets for breast cancer treatment.
- Clinical Significance: The study uncovered the critical role of neutrophils in breast cancer progression and found that neutrophil-related gene expression correlates with lower survival rates in breast cancer patients, providing new biomarkers for prognosis assessment.
Research Value
This study not only deepens our understanding of the role of neutrophils in the tumor microenvironment but also provides new insights and potential targets for breast cancer treatment and prognosis assessment. By revealing the complex signaling network between neutrophils and tumor cells, this research lays an important foundation for developing therapeutic strategies targeting the tumor microenvironment.