title: Identification of TAX2 peptide as a new unpredicted anti-cancer agent.
abstract: The multi-modular glycoprotein thrombospondin-1 (TSP-1) is considered as a key actor within the tumor microenvironment. Besides, TSP-1 binding to CD47 is widely reported to regulate cardiovascular function as it promotes vasoconstriction and angiogenesis limitation. Therefore, many studies focused on targeting TSP-1:CD47 interaction, aiming for up-regulation of physiological angiogenesis to enhance post-ischemia recovery or to facilitate engraftment. Thus, we sought to identify an innovative selective antagonist for TSP-1:CD47 interaction. Protein-protein docking and molecular dynamics simulations were conducted to design a novel CD47-derived peptide, called TAX2. TAX2 binds TSP-1 to prevent TSP-1:CD47 interaction, as revealed by ELISA and co-immunoprecipitation experiments. Unexpectedly, TAX2 inhibits in vitro and ex vivo angiogenesis features in a TSP-1-dependent manner. Consistently, our data highlighted that TAX2 promotes TSP-1 binding to CD36-containing complexes, leading to disruption of VEGFR2 activation and downstream NO signaling. Such unpredicted results prompted us to investigate TAX2 potential in tumor pathology. A multimodal imaging approach was conducted combining histopathological staining, MVD, MRI analysis and μCT monitoring for tumor angiography longitudinal follow-up and 3D quantification. TAX2 in vivo administrations highly disturb syngeneic melanoma tumor vascularization inducing extensive tumor necrosis and strongly inhibit growth rate and vascularization of human pancreatic carcinoma xenografts in nude mice.
authors.affiliation: Université de Reims Champagne-Ardenne, Laboratoire SiRMa, UFR Sciences Exactes et Naturelles, Reims, France.|CNRS UMR 7369, Matrice Extracellulaire et Dynamique Cellulaire, MEDyC, Reims, France.|SATT Nord, Lille, France.
authors.forename: Albin
authors.initials: A
authors.lastname: Jeanne
authors.affiliation: Université de Reims Champagne-Ardenne, Laboratoire SiRMa, UFR Sciences Exactes et Naturelles, Reims, France.|Université de Strasbourg, CNRS UMR 7213, Illkirch, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Sick
authors.affiliation: Université de Reims Champagne-Ardenne, Laboratoire SiRMa, UFR Sciences Exactes et Naturelles, Reims, France.|CNRS UMR 7369, Matrice Extracellulaire et Dynamique Cellulaire, MEDyC, Reims, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Devy
authors.affiliation: Institut des Biomolécules Max Mousseron (IBMM), CNRS UMR 5247, Université de Montpellier, Ecole Normale Supérieure de Chimie de Montpellier, Faculté de Pharmacie, Montpellier, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Floquet
authors.affiliation: CNRS UMR 7369, Matrice Extracellulaire et Dynamique Cellulaire, MEDyC, Reims, France.|Plateforme de Modélisation Moléculaire Multi-Échelle (P3M), Université de Reims Champagne-Ardenne, Reims, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Belloy
authors.affiliation: Université de Reims Champagne-Ardenne, Laboratoire SiRMa, UFR Sciences Exactes et Naturelles, Reims, France.|CNRS UMR 7369, Matrice Extracellulaire et Dynamique Cellulaire, MEDyC, Reims, France.
authors.forename: Louis
authors.initials: L
authors.lastname: Theret
authors.affiliation: CNRS UMR 7369, Matrice Extracellulaire et Dynamique Cellulaire, MEDyC, Reims, France.|CHU de Reims, Laboratoire Central d'Anatomie et de Cytologie Pathologiques, Reims, France.
authors.forename: Camille
authors.initials: C
authors.lastname: Boulagnon-Rombi
authors.affiliation: CNRS UMR 7369, Matrice Extracellulaire et Dynamique Cellulaire, MEDyC, Reims, France.|CHU de Reims, Laboratoire Central d'Anatomie et de Cytologie Pathologiques, Reims, France.
authors.forename: Marie-Danièle
authors.initials: MD
authors.lastname: Diebold
authors.affiliation: CNRS UMR 7369, Matrice Extracellulaire et Dynamique Cellulaire, MEDyC, Reims, France.|Plateforme de Modélisation Moléculaire Multi-Échelle (P3M), Université de Reims Champagne-Ardenne, Reims, France.
authors.forename: Manuel
authors.initials: M
authors.lastname: Dauchez
authors.affiliation: Université de Reims Champagne-Ardenne, Laboratoire SiRMa, UFR Sciences Exactes et Naturelles, Reims, France.|CNRS UMR 7369, Matrice Extracellulaire et Dynamique Cellulaire, MEDyC, Reims, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Martiny
authors.affiliation: Université de Reims Champagne-Ardenne, Laboratoire SiRMa, UFR Sciences Exactes et Naturelles, Reims, France.|CNRS UMR 7369, Matrice Extracellulaire et Dynamique Cellulaire, MEDyC, Reims, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Schneider
authors.affiliation: Université de Reims Champagne-Ardenne, Laboratoire SiRMa, UFR Sciences Exactes et Naturelles, Reims, France.|CNRS UMR 7369, Matrice Extracellulaire et Dynamique Cellulaire, MEDyC, Reims, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Dedieu
mesh_terms: D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D018955:CD36 Antigens / Q000378:metabolism; D002277:Carcinoma / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D017076:Computer-Aided Design; D015195:Drug Design; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008279:Magnetic Resonance Imaging; D008546:Melanoma, Experimental / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D058990:Molecular Targeted Therapy; D009336:Necrosis; D009389:Neovascularization, Pathologic; D009569:Nitric Oxide / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010455:Peptides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D010456:Peptides, Cyclic / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding; D015398:Signal Transduction / Q000187:drug effects; D019700:Thrombospondin 1 / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D055114:X-Ray Microtomography; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D018955:CD36 Antigens; D010455:Peptides; D010456:Peptides, Cyclic; D019700:Thrombospondin 1; C000607691:cyclic TAX2 peptide; D009569:Nitric Oxide; C000588866:KDR protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: CD36; CD47; TSP-1; angiogenesis; cancer