Stalin, Jimmy Coquoz, Oriana Jeitziner Marcone, Rachel Jemelin, Stéphane Desboeufs, Nina Delorenzi, Mauro Blot-Chabaud, Marcel Beat, Imhof Ruegg, Curzio 2023 The melanoma cell adhesion molecule, shed from endothelial and cancer cells, is a soluble growth factor that induces tumor angiogenesis and growth. However, the molecular mechanism accounting for its generation in a tumor context is still unclear. To investigate this mechanism, we performed in vitro experiments with endothelial/cancer cells, gene expression analyses on datasets from human colorectal tumor samples, and applied pharmacological methods in vitro/ in vivo with mouse and human colorectal cancer cells. We found that soluble MCAM generation is governed by ADAM17 proteolytic activity and NOX1-regulating ADAM17 expression. The treatment of colorectal tumor-bearing mice with pharmacologic NOX1 inhibitors or tumor growth in NOX1-deficient mice reduced the blood concentration of soluble MCAM and abrogated the anti-tumor effects of anti-soluble MCAM antibodies while ADAM17 pharmacologic inhibitors reduced tumor growth and angiogenesis in vivo. Especially, the expression of MCAM, NOX1, and ADAM17 was more prominent in the angiogenic, colorectal cancer-consensus molecular subtype 4 where high MCAM expression correlated with angiogenic and lymphangiogenic markers. Finally, we demonstrated that soluble MCAM also acts as a lymphangiogenic factor in vitro. These results identify a role for NOX1/ADAM17 in soluble MCAM generation, with potential clinical therapeutic relevance to the aggressive, angiogenic CMS4 colorectal cancer subtype. application/pdf https://folia.unifr.ch/global/documents/327473 https://folia.unifr.ch/documents/327473/files/biomedicines-11-03185-1_0.pdf eng info:eu-repo/semantics/altIdentifier/doi/10.3390/biomedicines11123185 info:eu-repo/semantics/altIdentifier/issn/2227-9059 info:eu-repo/semantics/openAccess CC BY Biomedicines. - MDPI AG. - 2023, vol. 11, no. 12, p. 3185 NADPH oxidases; melanoma cell adhesion molecule angiogenesis lymphangiogenesis pharmacologic inhibitors colorectal tumor bioinformatic analysis. info:eu-repo/classification/udc/616 Targeting of the NOX1/ADAM17 Enzymatic Complex Regulates Soluble MCAM-Dependent Pro-Tumorigenic Activity in Colorectal Cancer http://purl.org/coar/resource_type/c_6501