Authors:

Serena C Thomas

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Metastasis is the leading cause of breast cancer-related mortality. However, the success of metastatic colonization is not solely determined by tumor cells' ability to disseminate; it is also influenced by the establishment of premetastatic niches within distant organs. Neutrophils promote lung metastasis by priming the premetastatic niche to make it a more hospitable environment for disseminating tumor cells. Atypical Chemokine Receptor 1 (ACKR1) is expressed on endothelial cells and is critical for neutrophil migration in inflammatory conditions, but its role has not previously been characterized in pre-metastatic niche formation. We hypothesize that eliminating this endothelial ACKR1 may reduce neutrophil extravasation into the lungs, thereby disrupting the formation of the pre-metastatic niche and decreasing metastasis. To study the role of endothelial ACKR1 in tumor cell and neutrophil extravasation, we analyzed the distribution of disseminating tumor cells and neutrophils relative to ACKR1-positive versus ACKR1-negative vessels in the lungs of orthotopic mammary tumor-bearing mice. To analyze disseminating tumor cells and extravasated neutrophils, we performed immunofluorescent staining of lung vasculature from immunocompetent mice implanted with £0771.LMB mammary tumor cells 28 days post-tumor injection. We developed a semi-automated workflow to analyze the distance between disseminated tumor cells, neutrophils, and their proximity within 50, 100, or 150 microns of ACKR1-positive or -negative venules. Our analysis revealed a significant increase in the average number of tumor cells within 50 microns of ACKR1-positive venules compared to ACKR1-negative venules. Similarly, neutrophil analysis showed a significant increase in neutrophils within 50 microns of ACKR1-positive venules. These findings demonstrate that both disseminated tumor cells and neutrophils preferentially localize near ACKR1-positive lung venules during breast cancer metastasis, suggesting that both cell types extravasate preferentially through ACKR1-expressing venules. Understanding this mechanism may open new avenues for therapeutic strategies aimed at mitigating breast cancer metastasis. SPODTOG SHS OHO OHH OSE SOOO OOOOH LOOCOOO PCOS OHOHO OO OCOOOOES

Source:

University of Illinois Chicago

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Co-authors:

Serena C Thomas