Tumor cell-derived lymphotoxin alpha triggers metastatic extravasation through TNFRs/cIAP1

Metastasis involves the interaction of the tumor, immune and endothelial cells. Cell death proteins, such as inhibitors of apoptosis proteins (IAPs), are critical players in survival, inflammation and permeability. Whether the use of Smac mimetics, which target cIAP1/2 for degradation would affect metastasis is unknown. We show Smac mimetics reduced metastasis due to the loss of cIAP1 but not cIAP2 in experimental metastasis models. The endothelial compartment rather than the immune cells was responsible for reduction of extravasation upon loss of cIAP1. Loss of cIAP1 in primary endothelial cells did not lead to cell death but resulted in an unresponsive endothelium barrier to permeability factors causing a reduction in tumor cell extravasation. Unexpectedly, the co-loss of TNFR1 and cIAP1 restored the tumor load. We were surprised to find lymphotoxin alpha (LTA), and not TNF, secreted by the tumor cells was critical for the extravasation. Using TCGA data, we found high levels of LTA mRNA expression correlated with decreased survival in kidney carcinoma and associated with advance disease stage. Our data suggest that Smac mimetics, targeting cIAP1/2, may reduce metastasis to the lung through a LTA/TNFR mechanism by altering the endothelial barrier and inhibiting the ability of tumor cells to extravasate.