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

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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.

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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

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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.

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Correspondence to Stéphane Dedieu.

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Jeanne, A., Boulagnon-Rombi, C., Devy, J. et al. Matricellular TSP-1 as a target of interest for impeding melanoma spreading: towards a therapeutic use for TAX2 peptide. Clin Exp Metastasis 33, 637–649 (2016). https://doi.org/10.1007/s10585-016-9803-0

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