Ephrin-B2–EphB4 communication mediates tumor–endothelial cell interactions during hematogenous spread to spinal bone in a melanoma metastasis model

• Published in: Oncogene Vol. 39; no. 47; pp. 7063 - 7075
• Main Authors: Broggini, Thomas, Piffko, Andras, Hoffmann, Christian J., Ghori, Adnan, Harms, Christoph, Adams, Ralf H., Vajkoczy, Peter, Czabanka, Marcus
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 19.11.2020; Nature Publishing Group
• Subjects: 631/67/322/803; 631/67/70; Animals; Apoptosis; Bone cancer; Bone growth; Bone Marrow - diagnostic imaging; Bone Marrow - pathology; Cancer; Cell Adhesion; Cell Biology; Cell Communication - drug effects; Cell Communication - genetics; Cell interactions; Cell Line, Tumor - transplantation; Cellular signal transduction; Compression; Development and progression; Endothelial cells; Endothelial Cells - pathology; Endothelium; Extravasation; Female; Genetic aspects; Health aspects; Human Genetics; Internal Medicine; Intravital Microscopy; Locomotion; Magnetic Resonance Imaging; Male; Medicine; Medicine & Public Health; Melanoma; Melanoma, Experimental - drug therapy; Melanoma, Experimental - secondary; Metastases; Metastasis; Mice; Mice, Knockout; Microscopy, Video; Morbidity; Oncology; Osteoblasts - pathology; Phenotypes; Protein tyrosine kinase; Pyrazoles - pharmacology; Pyrazoles - therapeutic use; Pyrimidines - pharmacology; Pyrimidines - therapeutic use; Receptor, EphB2 - genetics; Receptor, EphB2 - metabolism; Receptor, EphB4 - antagonists & inhibitors; Receptor, EphB4 - metabolism; Skin Neoplasms - drug therapy; Skin Neoplasms - pathology; Skull - pathology; Spinal cord; Spinal Cord Compression - diagnosis; Spinal Cord Compression - etiology; Spinal diseases; Spinal Neoplasms - complications; Spinal Neoplasms - diagnosis; Spinal Neoplasms - drug therapy; Spinal Neoplasms - secondary; Spine - cytology; Spine - diagnostic imaging; Spine - pathology; Tumor cells; Germany
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-020-01473-y

Metastases account for the majority of cancer deaths. Bone represents one of the most common sites of distant metastases, and spinal bone metastasis is the most common source of neurological morbidity in cancer patients. During metastatic seeding of cancer cells, endothelial–tumor cell interactions govern extravasation to the bone and potentially represent one of the first points of action for antimetastatic treatment. The ephrin-B2–EphB4 pathway controls cellular interactions by inducing repulsive or adhesive properties, depending on forward or reverse signaling. Here, we report that in an in vivo metastatic melanoma model, ephrin-B2-mediated activation of EphB4 induces tumor cell repulsion from bone endothelium, translating in reduced spinal bone metastatic loci and improved neurological function. Selective ephrin-B2 depletion in endothelial cells or EphB4 inhibition increases bone metastasis and shortens the time window to hind-limb locomotion deficit from spinal cord compression. EphB4 overexpression in melanoma cells ameliorates the metastatic phenotype and improves neurological outcome. Timely harvesting of bone tissue after tumor cell injection and intravital bone microscopy revealed less tumor cells attached to ephrin-B2-positive endothelial cells. These results suggest that ephrin-B2–EphB4 communication influences bone metastasis formation by altering melanoma cell repulsion/adhesion to bone endothelial cells, and represents a molecular target for therapeutic intervention.