Extracellular ATP drives breast cancer cell migration and metastasis via S100A4 production by cancer cells and fibroblasts

Our previous work has demonstrated that extracellular ATP is an important pro-invasive factor, and in this study, we tapped into a possible mechanism involved. We discovered that ATP could upregulate both the intracellular expression and secretion of S100A4 in breast cancer cells and fibroblasts. Apart from stimulating breast cancer cell motility via intracellular S100A4, ATP enhanced the ability of breast cancer cells to transform fibroblasts into cancer-associated fibroblast (CAF)-like cells, which in turn secreted S100A4 to further promote cancer cell motility. Both apyrase and niclosamide treatments could inhibit metastasis of inoculated tumors to lung, liver and kidney in mice model, and CAFs from these treated tumors exhibited weakened migration-stimulating capacity for breast cancer cells. Collectively, our data indicate that extracellular ATP promotes the interactions between breast cancer cells and fibroblasts, which work collaboratively via production of S100A4 to exacerbate breast cancer metastasis. A schematic representation of the potential mode of interaction between cancer cells and fibroblasts upon extracellular ATP stimulation. Extracellular ATP in the tumor microenvironment acts not only on breast cancer cells but also on fibroblasts. ①ATP promotes cancer cell pseudopodia formation and migration through upregulation of intracellular S100A4, and ②enhances the ability of cancer cells to transform fibroblasts into cancer-associated fibroblasts (CAF)-like cells (also termed activated fibroblasts), which in turn ③secret S100A4 to act on cancer cells and exacerbate tumor migration. [Display omitted] •Extracellular ATP acts on both breast cancer cells and fibroblasts.•ATP stimulates the migration of breast cancer cells via production of S100A4.•ATP promotes breast cancer cells to transform fibroblasts into CAF-like cells.•The secreted S100A4 by activated fibroblasts promotes cancer cell migration.