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.
Highlights
Besides its architectural role, extracellular matrix (ECM) is commonly known to be involved in a wide range of physiological and pathological functions [1], with cell-ECM interaction actively taking part in cancer progression [2]
And 1D, molecular dynamics experiments highlighted that the interacting sequence is less stretchy in the cyclic peptide. This correlates with increased stability over time and a conservation of the helical native conformation, suggesting an increased ability of cyclic TAX2 to bind TSP-1 cell-binding domain (CBD) compared to the linear analogue
We demonstrate that the in silico-designed peptide, called TAX2, exhibits unexpected anti-angiogenic properties in vitro and ex vivo and induces extensive melanoma tumor necrosis in vivo by inhibiting tumor angiogenesis
Summary
Extracellular matrix (ECM) is commonly known to be involved in a wide range of physiological and pathological functions [1], with cell-ECM interaction actively taking part in cancer progression [2]. TSP-1 is a ubiquitously expressed multimodular protein of high molecular weight secreted as a disulfide-linked 450 kDa homotrimer. The ability of TSP-1 to bind a wide variety of ligands such as cell membrane receptors or ECM molecules allows it to mediate cell-cell and cell-ECM interactions [4], conferring multifaceted functionalities. TSP-1 is involved in inflammation, immune response [10] and is widely known as an endogenous inhibitor of angiogenesis [11,12,13,14] by interacting with stromal cells
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