The spatial distribution of resident and monocytes derived macrophages in experimental brain metastases

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Avinoam Ratzabi1, Itai M Caspit1,2, Irina Gumennaia1,2, Kaveri Banerjee1, Steffen Jung3, Pablo Blinder1,2, and Reuven Stein1,2

 

1 Department of Neurobiology, School of Neurobiology, Biochemistry and Biophysics, George S. Wise Faculty of Life Sciences, Tel Aviv University, Israel .

2 Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel.

3 Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot, Israel

 

Background: Brain metastases (BrM) occur in 10%-25% of cancer patients, making up over half of adult brain tumors. Despite advances, median survival remains under a year. Microglia (Mg) and monocyte-derived macrophages (MDM) respond to BrM, but their specific roles in tumor progression are unclear. Whether tumor-associated microglia (TA-Mg) and tumor-associated MDM (TA-MDM) (collectively termed TAMs) impact BrM similarly to gliomas and how metastatic cell origin and brain location influence these responses, particularly their spatial distribution, requires further investigation.
 

Methods: To distinguish between TA-Mg and TA-MDM, we employed genetic tracing mouse models that enable us to trace these cells specifically. Experimental BrM of melanoma (RET), lung carcinoma (D122), and breast cancer (EO771) were established in these mice by intracardiac or intracranial injection.
 

Results: Our results show that Mg are the first myeloid cells that respond to the occurrence of early-stage parenchymal metastatic lesions of lung and breast BrM. They proliferate, contact the tumor cells, are activated, and accumulate at the surface of the tumors. While some MDMs are present in small masses, their density is lower than that of Mg. In larger tumors, Mg density decreases, and MDMs outnumber them inside the tumor. However, in melanoma Ret models, neither Mg nor MDM accumulate, suggesting a limited functional role.
 

Conclusions: The results also show that the activation, distribution, and ratio of TA-Mg to TA-MDM vary across BrM of different sizes and origins and in different brain regions, indicating that tumor cell genetics influence TAM behavior in a brain-region-specific manner.