SNAIL1 action in tumor cells influences macrophage polarization and metastasis in breast cancer through altered GM-CSF secretion

The EMT inducer SNAIL1 regulates breast cancer metastasis and its expression in human primary breast tumor predicts for poor outcomes. During tumor progression SNAIL1 has multiple effects in tumor cells that can impact metastasis. An inflammatory tumor microenvironment also impacts metastasis and recently SNAIL1 has been implicated as modulating the secretion of cytokines that can influence the tumor immune infiltrate. Using a spontaneous genetic model of breast cancer metastasis and syngeneic orthotopic transplant experiments we show that the action of SNAIL1 in primary breast tumor cells is required for breast tumor growth and metastasis. It does so, in part, by regulating production of GM-CSF, IL1α, IL-6, and TNFα by breast cancer cells. The SNAIL1-dependent tumor cell secretome modulates the primary tumor-associated macrophage (TAM) polarization. GM-CSF alone modulates TAM polarization and impacts breast cancer metastasis in vivo. This study highlights another role for breast tumor SNAIL1 in cancer progression to metastasis—modulation of the immune microenvironment of primary breast tumors.