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Updated: Aug 31, 2025
Studying the Role of Alveolar Macrophages in Breast Cancer Metastasis
Published on: June 26, 2016
Single-cell RNA-sequencing identifies anti-cancer immune phenotypes in the early lung metastatic niche during breast
Sophia M Orbach1, Michael D Brooks2, Yining Zhang3
1Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA.
Abstract:
Microenvironmental changes in the early metastatic niche may be exploited to identify therapeutic targets to inhibit secondary tumor formation and improve disease outcomes. We dissected the developing lung metastatic niche in a model of metastatic, triple-negative breast cancer using single-cell RNA-sequencing. Lungs were extracted from mice at 7-, 14-, or 21 days after tumor inoculation corresponding to the pre-metastatic, micro-metastatic, and metastatic niche, respectively. The progression of the metastatic niche was marked by an increase in neutrophil infiltration (5% of cells at day 0 to 81% of cells at day 21) and signaling pathways corresponding to the hallmarks of cancer. Importantly, the pre-metastatic and early metastatic niche were composed of immune cells with an anti-cancer phenotype not traditionally associated with metastatic disease. As expected, the metastatic niche exhibited pro-cancer phenotypes. The transition from anti-cancer to pro-cancer phenotypes was directly associated with neutrophil and monocyte behaviors at these time points. Predicted metabolic, transcription factor, and receptor-ligand signaling suggested that changes in the neutrophils likely induced the transitions in the other immune cells. Conditioned medium generated by cells extracted from the pre-metastatic niche successfully inhibited tumor cell proliferation and migration in vitro and the in vivo depletion of pre-metastatic neutrophils and monocytes worsened survival outcomes, thus validating the anti-cancer phenotype of the developing niche. Genes associated with the early anti-cancer response could act as biomarkers that could serve as targets for the treatment of early metastatic disease. Such therapies have the potential to revolutionize clinical outcomes in metastatic breast cancer.
Insights
Early breast cancer metastasis involves immune cells with anti-cancer properties. Targeting these early immune changes, particularly neutrophils, may offer new therapeutic strategies to inhibit secondary tumor growth.
Area of Science:
- Oncology
- Immunology
- Genomics
Background:
- The tumor microenvironment plays a critical role in cancer metastasis.
- Understanding the early stages of metastatic niche formation is key to developing effective therapies.
Purpose of the Study:
- To investigate the cellular and molecular changes within the developing lung metastatic niche in triple-negative breast cancer.
- To identify potential therapeutic targets for inhibiting secondary tumor formation.
Main Methods:
- Single-cell RNA-sequencing of lung tissue at different time points post-tumor inoculation (pre-metastatic, micro-metastatic, metastatic).
- Analysis of immune cell infiltration, phenotype transitions, and signaling pathways.
- In vitro and in vivo validation of identified cellular behaviors.
Main Results:
- Metastatic niche progression is characterized by increased neutrophil infiltration and pro-cancer signaling.
- Early metastatic niches contain immune cells with an anti-cancer phenotype, influenced by neutrophil and monocyte activity.
- Pre-metastatic niche components inhibited tumor cell growth in vitro, and their depletion worsened survival in vivo.
Conclusions:
- The early metastatic niche exhibits an anti-cancer immune phenotype that can be therapeutically exploited.
- Neutrophils and monocytes play a crucial role in modulating the immune response within the developing metastatic niche.
- Genes associated with the early anti-cancer response may serve as biomarkers and therapeutic targets for metastatic breast cancer.
