Bone Vascular Niche E-selectin Induces Mesenchymal-Epithelial Transition and Wnt Activation in Cancer Cells to Promote Bone Metastasis

How disseminated tumor cells (DTCs) engage specific stromal components in distant organs for survival and outgrowth is a critical but poorly understood step of the metastatic cascade. Previous studies have demonstrated the importance of the epithelial-mesenchymal transition (EMT) in promoting the cancer stem cell properties needed for metastasis initiation, while the reverse process of mesenchymal-epithelial transition (MET) is required for metastatic outgrowth. Here we report that this paradoxical requirement for simultaneous induction of both MET and cancer stem cell traits in DTCs is provided by bone vascular niche E-selectin, whose direct binding to cancer cells promotes bone metastasis by inducing MET and activating Wnt signaling. E-selectin binding activity mediated by α1–3 Fucosyltransferases Fut3/Fut6 and Glg1 are instrumental to the formation of bone metastasis. These findings provide unique insights into the functional role of E-selectin as a component of the vascular niche critical for metastatic colonization in bone.