Astrocytes from the brain microenvironment alter migration and morphology of metastatic breast cancer cells

Abstract

Tumor cellmetastasis to the brain involves cellmigration through biochemically and physically complex microenvironments at the blood-brain barrier (BBB). The current understanding of tumor cellmigration across the BBB is limited. We hypothesize that an interplay between biochemical cues and physical cues at the BBB affects the mechanisms of brain metastasis. We found that astrocyte conditioned medium(ACM) applied directly to tumor cells increased tumor cell velocity, induced elongation, and promoted act in stress fiber organization. Notably, treatment of the extra cellular matrix with ACM led to even more significant increases in tumor cell velocity in comparison with ACM treatment of cells directly. Furthermore, inhibiting matrix metalloproteinases in ACM reversed ACM's effect on tumor cells. The effects of AC Mon tumor cell morphology and migration also depended on astrocytes' activation state. Finally, using amicrofluidic device, we found that the effects of ACM were abrogated in confinement. Overall, our work demonstrates that astrocyte-secreted factors alter migration and morphology of metastatic breast tumor cells, and this effect depends on the cells' mechanical microenvironment.