ESDN inhibits melanoma progression by blocking E-selectin expression in endothelial cells via STAT3

• Published in: Cancer letters 2021-07, Vol.510, p.13-23
• Main Authors: Coppo, Roberto, Orso, Francesca, Virga, Federico, Dalmasso, Alberto, Baruffaldi, Desirée, Nie, Lei, Clapero, Fabiana, Dettori, Daniela, Quirico, Lorena, Grassi, Elena, Defilippi, Paola, Provero, Paolo, Valdembri, Donatella, Serini, Guido, Sadeghi, Mehran M., Mazzone, Massimiliano, Taverna, Daniela
• Format: Article
• Language: English
• Subjects: Adhesion; Animals; Cimetidine; Disease Models, Animal; Disease Progression; E-Selectin - antagonists & inhibitors; E-Selectin - biosynthesis; E-Selectin - metabolism; Endothelial Cells - metabolism; ESDN; Humans; Melanoma - genetics; Melanoma - metabolism; Melanoma - pathology; Melanoma metastasis; Membrane Proteins - metabolism; Mice; STAT3 Transcription Factor - metabolism; Tumor Microenvironment
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2021.04.005

An interactive crosstalk between tumor and stroma cells is essential for metastatic melanoma progression. We evidenced that ESDN/DCBLD2/CLCP1 plays a crucial role in endothelial cells during the spread of melanoma. Precisely, increased extravasation and metastasis formation were revealed in ESDN-null mice injected with melanoma cells, even if the primary tumor growth, vessel permeability, and angiogenesis were not enhanced. Interestingly, improved adhesion of melanoma cells to ESDN-depleted endothelial cells was observed, due to the presence of higher levels of E-selectin transcripts/proteins in ESDN-defective cells. In accordance with these results, anticorrelation was observed between ESDN and E-selectin in human endothelial cells. Most importantly, our data revealed that cimetidine, an E-selectin inhibitor, was able to block cell adhesion, extravasation, and metastasis formation in ESDN-null mice, underlying a major role of ESDN in E-selectin transcription upregulation, which according to our data, may presumably be linked to STAT3. Based on our results, we propose a protective role for ESDN during the spread of melanoma and reveal its therapeutic potential. •ESDN/DCBLD2/CLCP1 in endothelial cells regulates adhesion, extravasation and metastatization of melanoma cells.•Melanoma cells adhere more to ESDN-depleted endothelial cells.•Increased E-selectin expression in ESDN-depleted cells favours melanoma adhesion to endothelial cells and extravasation.•ESDN regulates E-selectin transcription via STAT3.