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Clinical & Experimental Metastasis

, Volume 33, Issue 7, pp 637–649 | Cite as

Matricellular TSP-1 as a target of interest for impeding melanoma spreading: towards a therapeutic use for TAX2 peptide

  • Albin Jeanne
  • Camille Boulagnon-Rombi
  • Jérôme Devy
  • Louis Théret
  • Caroline Fichel
  • Nicole Bouland
  • Marie-Danièle Diebold
  • Laurent Martiny
  • Christophe Schneider
  • Stéphane Dedieu
Research Paper

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.

Keywords

Thrombospondin-1 CD47 TAX2 peptide Melanoma Metastasis Innovative therapeutic strategy 

Abbreviations

3TSR

Three thrombospondin-1 type 1 repeats

ECM

Extracellular matrix

EMT

Epithelial-to-mesenchymal transition

MST

Microscale thermophoresis

PPI

Protein-protein interaction

SIRPα

Signal-regulatory protein-alpha

SPR

Surface plasmon resonance

TSP-1

Thrombospondin-1

µCT

Micro-computed tomography

Notes

Acknowledgments

The authors acknowledge supports from Centre National de la Recherche Scientifique (CNRS), Région Champagne-Ardenne and SATT Nord. AJ was recipient of grants from the Ministère de l’Enseignement Supérieur et de la Recherche (2010-2013). The authors acknowledge A. Thomachot for editorial assistance.

Supplementary material

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Copyright information

© Springer Science+Business Media Dordrecht 2016

Authors and Affiliations

  • Albin Jeanne
    • 1
    • 2
    • 3
  • Camille Boulagnon-Rombi
    • 2
    • 4
  • Jérôme Devy
    • 1
    • 2
  • Louis Théret
    • 1
    • 2
  • Caroline Fichel
    • 5
  • Nicole Bouland
    • 5
  • Marie-Danièle Diebold
    • 2
    • 4
  • Laurent Martiny
    • 1
    • 2
  • Christophe Schneider
    • 1
    • 2
  • Stéphane Dedieu
    • 1
    • 2
  1. 1.Laboratoire SiRMa, Campus Moulin de La Housse, Université de Reims Champagne-Ardenne (URCA), UFR Sciences Exactes Et NaturellesReims Cedex 2France
  2. 2.CNRS UMR 7369, Unité Matrice Extracellulaire Et Dynamique Cellulaire, MEDyCReimsFrance
  3. 3.SATT NordLilleFrance
  4. 4.CHU de Reims, Laboratoire Central D’Anatomie Et de Cytologie PathologiquesReimsFrance
  5. 5.Université de Reims Champagne-Ardenne, Laboratoire D’Anatomie Pathologique, UFR MédecineReimsFrance

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