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Updated: Apr 2, 2026
A Macrophage-Tumor Spheroid Co-Invasion Assay
Published on: January 24, 2025
Brain metastases exhibit distinct spatial patterns of resident and infiltrating macrophages
Avinoam Ratzabi1, Itai M Caspit1,2, Ira Telechi1,2
1Department of Neurobiology, School of Neurobiology, Biochemistry and Biophysics, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
Abstract:
Brain metastases (BrM) are a leading cause of morbidity and mortality, arising in multiple brain compartments. BrM colonization and progression are shaped by interactions with distinct tumor-associated macrophage (TAM) subsets, including microglia (MG), monocyte-derived macrophages (MDM), and border-associated macrophages (BAM). While transcriptomes of TAM have been characterized in detail, their spatial distribution, abundance, and compartment-specific composition -particularly in relation to BrM size and the cancer origin-remain poorly defined. Here, we performed a comprehensive spatial analysis of TAM subtypes across brain regions using experimental BrM models of lung and breast cancer, as well as melanoma. We distinguished TAM subsets by both origin and location, employing genetically traceable mouse models. We observed expansion of MG and BAM, as well as MDM infiltration associated with BrM, albeit with distinct compositions. Parenchymal BrM contained both MG and MDM, whereas ventricular and leptomeningeal BrM contained BAM and MDM but lacked MG. TAM abundance varied with BrM size, compartment, and cancer type: MG predominated in early parenchymal lesions, with MDM becoming dominant as tumors grew. Notably, melanoma BrM exhibited markedly reduced MDM infiltration compared with lung and breast cancer BrM. These findings highlight the need to tailor TAM-targeted therapies not only to the primary tumor type but also to the brain compartment affected. A deeper understanding of TAM dynamics across compartments may improve the precision and efficacy of BrM treatments.
Insights
Tumor-associated macrophages (TAMs) in brain metastases (BrM) vary by location and cancer type. Targeting these macrophages requires considering the specific brain compartment and cancer origin for effective treatment.
Area of Science:
- Neuro-oncology
- Immunology
- Cancer Biology
Background:
- Brain metastases (BrM) are a significant cause of cancer-related death.
- Tumor-associated macrophages (TAMs), including microglia (MG), monocyte-derived macrophages (MDM), and border-associated macrophages (BAM), influence BrM progression.
- The spatial distribution and composition of TAMs in BrM are not well understood.
Purpose of the Study:
- To comprehensively analyze the spatial distribution, abundance, and compartment-specific composition of TAM subtypes in experimental BrM models.
- To investigate how TAM composition varies with BrM size, brain compartment, and primary cancer type (lung, breast, melanoma).
Main Methods:
- Utilized genetically traceable mouse models to distinguish TAM subsets by origin and location.
- Performed spatial analysis of TAM subtypes across different brain regions in experimental BrM models.
- Correlated TAM abundance and composition with BrM size, compartment, and cancer type.
Main Results:
- Observed distinct TAM compositions in different brain compartments: parenchymal BrM contained MG and MDM, while ventricular/leptomeningeal BrM had BAM and MDM but lacked MG.
- TAM abundance varied with BrM size and compartment; MG predominated in early lesions, with MDM increasing as tumors grew.
- Melanoma BrM showed significantly less MDM infiltration compared to lung and breast cancer BrM.
Conclusions:
- TAM subtypes and their distribution are compartment-specific and influenced by cancer type and BrM size.
- Therapeutic strategies targeting TAMs in BrM should be tailored to the specific brain compartment and primary tumor.
- Understanding TAM dynamics across brain compartments is crucial for improving BrM treatment precision and efficacy.
