Abstract
Formation of metastases is the major cause of death in patients diagnosed with cancer. It is a complex multistep process, including tumor cell migration, intravasation, survival in the circulation, and extravasation. Previously it was shown that tumor cell-induced endothelial necroptosis promotes tumor cell extravasation and metastasis. Here, we identified endothelial TGF-β-activated kinase 1 (TAK1) as a critical regulator of endothelial necroptosis and metastasis. Human and murine endothelial cells lacking TAK1 exhibit higher levels of necroptosis both in vitro and in vivo, and mice with endothelial cell-specific loss of TAK1 are more prone to form metastases. Endothelial RIPK3, a key component of the necroptotic machinery, was upregulated in mice with endothelial TAK1-deficiency, and endothelial knockout of RIPK3 reverted the effects of TAK1-deficiency. Moreover, altered expression levels of TAK1 and RIPK3 in pulmonary endothelial cells of mice bearing primary tumors correlated with increased endothelial necroptosis and metastasis. Together, our data suggest an important protective role for endothelial TAK1 in tumor progression by keeping endothelial necroptosis in check.