Permeable Lung Vasculature Creates Chemoresistant Endothelial Niche by Producing SERPINE1 at Breast Cancer Metastatic Sites

Abstract

Chemotherapy resistance remains a major obstacle for eradicating metastatic cancer cells in distant organs. We identified that endothelial cells (ECs) in the lungs, where breast cancer cells often metastasize, form a chemoresistant perivascular niche for disseminated breast cancer cells. By investigating the lung EC secretome activated by metastasis, we found that serine protease inhibitor family E member 1 (SERPINE1), encoded by Serpine1, is upregulated in metastasis-associated lung ECs. This upregulation shields cancer cells from paclitaxel-induced apoptosis and promotes cancer stem cell properties. Serpine1 expression appears to be driven by YAP-TEAD activation in lung ECs that lose cell–cell contact, a phenomenon associated with increased vascular permeability in lungs affected by metastasis. Crucially, pharmacological inhibition of SERPINE1 enhances the chemotherapy sensitivity of metastatic breast cancer cells in the lung. Overall, our findings underscore the pivotal role of the vascular niche, which produces SERPINE1, in conferring chemoresistance to breast cancer cells during metastatic progression in the lungs.