title: Matricellular TSP-1 as a target of interest for impeding melanoma spreading: towards a therapeutic use for TAX2 peptide.
abstract: Thrombospondin-1 (TSP-1) is a matricellular glycoprotein known for being highly expressed within a tumor microenvironment, where it promotes an aggressive phenotype particularly by interacting with the CD47 cell-surface receptor. While it originates from the stromal compartment in many malignancies, melanoma is an exception as invasive and metastatic melanoma cells overexpress TSP-1. We recently demonstrated that a new molecular agent that selectively prevents TSP-1 binding to CD47, called TAX2, exhibits anti-cancer properties when administered systemically by decreasing viable tumor tissue within subcutaneous B16 melanoma allografts. At the same time, emerging evidence was published suggesting a contribution of TSP-1 in melanoma metastatic dissemination and resistance to treatment. Through a comprehensive systems biology approach based on multiple genomics and proteomics databases analyses, we first identified a TSP-1-centered interaction network that is overexpressed in metastatic melanoma. Then, we investigated the effects of disrupting TSP-1:CD47 interaction in A375 human malignant melanoma xenografts. In this model, TAX2 systemic administrations induce tumor necrosis by decreasing intra-tumoral blood flow, while concomitantly making tumors less infiltrative. Besides, TAX2 treatment also drastically inhibits B16F10 murine melanoma cells metastatic dissemination and growth in a syngeneic experimental model of lung metastasis, as demonstrated by histopathological analyses as well as longitudinal and quantitative µCT follow-up of metastatic progression. Altogether, the results obtained by combining bioinformatics and preclinical studies strongly suggest that targeting TSP-1/CD47 axis may represent a valuable therapeutic alternative for hampering melanoma spreading.
authors.affiliation: Laboratoire SiRMa, Campus Moulin de La Housse, Université de Reims Champagne-Ardenne (URCA), UFR Sciences Exactes Et Naturelles, BP 1039, 51687, Reims Cedex 2, France.|CNRS UMR 7369, Unité Matrice Extracellulaire Et Dynamique Cellulaire, MEDyC, Reims, France.|SATT Nord, Lille, France.
authors.forename: Albin
authors.initials: A
authors.lastname: Jeanne
authors.affiliation: CNRS UMR 7369, Unité 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: Laboratoire SiRMa, Campus Moulin de La Housse, Université de Reims Champagne-Ardenne (URCA), UFR Sciences Exactes Et Naturelles, BP 1039, 51687, Reims Cedex 2, France.|CNRS UMR 7369, Unité Matrice Extracellulaire Et Dynamique Cellulaire, MEDyC, Reims, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Devy
authors.affiliation: Laboratoire SiRMa, Campus Moulin de La Housse, Université de Reims Champagne-Ardenne (URCA), UFR Sciences Exactes Et Naturelles, BP 1039, 51687, Reims Cedex 2, France.|CNRS UMR 7369, Unité Matrice Extracellulaire Et Dynamique Cellulaire, MEDyC, Reims, France.
authors.forename: Louis
authors.initials: L
authors.lastname: Théret
authors.affiliation: Université de Reims Champagne-Ardenne, Laboratoire D'Anatomie Pathologique, UFR Médecine, Reims, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Fichel
authors.affiliation: Université de Reims Champagne-Ardenne, Laboratoire D'Anatomie Pathologique, UFR Médecine, Reims, France.
authors.forename: Nicole
authors.initials: N
authors.lastname: Bouland
authors.affiliation: CNRS UMR 7369, Unité 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: Laboratoire SiRMa, Campus Moulin de La Housse, Université de Reims Champagne-Ardenne (URCA), UFR Sciences Exactes Et Naturelles, BP 1039, 51687, Reims Cedex 2, France.|CNRS UMR 7369, Unité Matrice Extracellulaire Et Dynamique Cellulaire, MEDyC, Reims, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Martiny
authors.affiliation: Laboratoire SiRMa, Campus Moulin de La Housse, Université de Reims Champagne-Ardenne (URCA), UFR Sciences Exactes Et Naturelles, BP 1039, 51687, Reims Cedex 2, France.|CNRS UMR 7369, Unité Matrice Extracellulaire Et Dynamique Cellulaire, MEDyC, Reims, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Schneider
authors.affiliation: Laboratoire SiRMa, Campus Moulin de La Housse, Université de Reims Champagne-Ardenne (URCA), UFR Sciences Exactes Et Naturelles, BP 1039, 51687, Reims Cedex 2, France. stephane.dedieu@univ-reims.fr.|CNRS UMR 7369, Unité Matrice Extracellulaire Et Dynamique Cellulaire, MEDyC, Reims, France. stephane.dedieu@univ-reims.fr.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Dedieu
mesh_terms: D000818:Animals; D051928:CD47 Antigen / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000556:secondary; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic; D010456:Peptides, Cyclic / Q000008:administration & dosage*; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D019700:Thrombospondin 1 / Q000037:antagonists & inhibitors / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays; D000096142:Cutaneous Malignant Melanoma
chemical_list: D051928:CD47 Antigen; D010456:Peptides, Cyclic; C000622216:TAX2 peptide; D019700:Thrombospondin 1
keywords: CD47; Innovative therapeutic strategy; Melanoma; Metastasis; TAX2 peptide; Thrombospondin-1