The atypical chemokine receptor 2 promotes breast cancer lung metastatization through modulation of the metastatic niche

.Introduction: The atypical chemokine receptor 2 (ACKR2) is a scavenger receptor for most inflammatory CC chemokines. It plays a protective role in chronic inflammation, autoimmunity and inflammation-related cancer. The aim of this project is to investigate the role of ACKR2 in primary tumor development and metastatization in different mouse model. Materials and methods: NeuT mice (overexpressing the rat oncogene Her2) crossed with ACKR2-/- mice and orthotopic and intravenous injection of the breast carcinoma cell line 4T1 in Wild Type (WT) and ACKR2-/- Balb/c mice. Tumors and metastasis were studied with in vivo imaging systems, immunohistochemistry and RT-PCR analysis; blood composition and metastatic organ infiltrate were studied with FACS analysis. Results: Tumor arising in ACKR2-/- NeuT mice showed a more aggressive phenotype when compared to WT NeuT mice. On the contrary, ACKR2-/- NeuT mice were protected from spontaneous lung metastasis. Absence of ACKR2 was also protective against spontaneous lung metastasis using the 4T1 orthotopic model of breast cancer but not in the intravenous injected model. Cytofluorimetric analysis indicated an increased of Ly6G+ polymorphonuclear cells and Ly6Chigh monocytes in the blood of ACKR2-/- in and in the pre-metastatic lungs with a concomitant decrease of these cells in the bone marrow during tumor progression. Conclusion: These results indicate that ACKR2 expression has a dual but opposite role in breast tumor, inhibiting primary tumor growth but promoting lung metastatization trough the regulation of leukocyte infiltration and activation in the premetastatic niche.