Conformation-dependent binding of a Tetrastatin peptide to αvβ3 integrin decreases melanoma progression through FAK/PI3K/Akt pathway inhibition

Lambert, Elise; Fuselier, Eloise; Ramont, Laurent; Brassart, Bertrand; Dukic, Sylvain; Oudart, Jean‐Baptiste; Dupont-Deshorgue, Aurélie; Sellier, Christèle; Machado, Carine; Dauchez, Manuel; Monboisse, Jean-Claude; Maquart, François‐Xavier; Baud, Stéphanie; Brassart‐Pasco, Sylvie

doi:10.1038/s41598-018-28003-x

Cited by 19 publications

(22 citation statements)

References 38 publications

(30 reference statements)

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“…the focal adhesion kinase (FAK)/PI3K/Akt/mTORC1 pathway, which is one of the main intracellular pathways involved in TME metabolic alterations. The inhibition leads to a decrease in the proliferative and invasive properties of tumor cells in various cancer models (27,33,38,56). The main receptors, biological activities, and molecular mechanisms identified for ECM bioactive fragments are reported in Table 1 and are illustrated in Figure 2.…”

Section: Extracellular Matrix-derived Fragments Influence Tumor Progrmentioning

confidence: 99%

Tumor Microenvironment: Extracellular Matrix Alterations Influence Tumor Progression

et al. 2020

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The tumor microenvironment (TME) is composed of various cell types embedded in an altered extracellular matrix (ECM). ECM not only serves as a support for tumor cell but also regulates cell-cell or cell-matrix cross-talks. Alterations in ECM may be induced by hypoxia and acidosis, by oxygen free radicals generated by infiltrating inflammatory cells or by tumor-or stromal cell-secreted proteases. A poorer diagnosis for patients is often associated with ECM alterations. Tumor ECM proteome, also named cancer matrisome, is strongly altered, and different ECM protein signatures may be defined to serve as prognostic biomarkers. Collagen network reorganization facilitates tumor cell invasion. Proteoglycan expression and location are modified in the TME and affect cell invasion and metastatic dissemination. ECM macromolecule degradation by proteases may induce the release of angiogenic growth factors but also the release of proteoglycan-derived or ECM protein fragments, named matrikines or matricryptins. This review will focus on current knowledge and new insights in ECM alterations, degradation, and reticulation through cross-linking enzymes and on the role of ECM fragments in the control of cancer progression and their potential use as biomarkers in cancer diagnosis and prognosis.

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Section: Extracellular Matrix-derived Fragments Influence Tumor Progrmentioning

confidence: 99%

Tumor Microenvironment: Extracellular Matrix Alterations Influence Tumor Progression

et al. 2020

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“…(c) Example of the generation of cryptic collagen epitopes generated by applying cell-mediated mechanical tension or contraction thereby unwinding or altering the triple-helical collagen structure The terms matrikine and matricryptin have been coined to describe small bioactive peptides or fragments of ECM molecules that exhibit distinct functions as compared to their intact parent protein (Ricard-Blum & Salza, 2014;Ricard-Blum & Vallet, 2016). A rapidly growing subgroup of these matrikine-like molecules (Ames et al, 2016;Colorado et al, 2000;Cretu et al, 2007;Gunda, Boosani, Verma, Guda, & Sudhakar, 2012;Kamphaus et al, 2000;Karagiannis & Popel, 2007;Koskimaki et al, 2010;Lambert et al, 2018;Lindsey et al, 2015;Maeshima et al, 2001;O'Reilly et al, 1997;Ortiz-Urda et al, 2005;Park & Scherer, 2012;Patel & Snelgrove, 2018;Ramchandran et al, 1999;Ricard-Blum & Salza, 2014;Ricard-Blum & Vallet, 2016;Weckmann et al, 2012;J. Xu et al, 2001;R.…”

Section: F I G U R Ementioning

confidence: 99%

Cryptic collagen elements as signaling hubs in the regulation of tumor growth and metastasis

Han

Caron

Brooks

2020

Journal Cellular Physiology

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Structural remodeling of the extracellular matrix is a well‐established process associated with tumor growth and metastasis. Tumor and stromal cells that compose the tumor mass function cooperatively to promote the malignant phenotype in part by physically interacting with intact and structurally altered matrix proteins. To this end, collagen represents the most abundant component of the extracellular matrix and is known to control the behavior of histologically distinct tumor types as well as a diversity of stromal cells. Although a significant molecular understanding has been established concerning how cellular interactions with intact collagen govern signaling pathways that control tumor progression, considerably less is known concerning how interactions with cryptic or hidden regions within remodeled collagen may selectively alter signaling cascades, or whether inhibition of these cryptic signaling pathways may represent clinically effective therapeutic strategies. Here, we review the emerging evidence concerning the possible mechanisms for the selective generation of cryptic or hidden elements within collagen and their potential cell surface receptors that may facilitate signal transduction. We discuss the concept that cellular communication links between cell surface receptors and these cryptic collagen elements may serve as functional signaling hubs that coordinate multiple signaling pathways operating within both tumor and stromal cells. Finally, we provide examples to help illustrate the possibility that direct targeting of these unique cryptic signaling hubs may lead to the development of more effective therapeutic strategies to control tumor growth and metastasis.

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“…Docking of QS-13 onto α 5 β 1 integrin (RCSB Protein Data Bank 3VI3) was performed using Autodock software (version 4.2; Morris et al, 2009). The docking parameters were as previously described (Lambert et al, 2018). The software was used with a fixed integrin and semi-flexible QS-13 ligand (the backbone was frozen as well as the amide links and guanidinium groups).…”

Section: Docking Experimentsmentioning

confidence: 99%

Angiogenesis Inhibition by a Short 13 Amino Acid Peptide Sequence of Tetrastatin, the α4(IV) NC1 Domain of Collagen IV

Vautrin-Glabik

Devy

Bour

et al. 2020

Front. Cell Dev. Biol.

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Angiogenesis is defined as the formation of new capillaries by sprouting from the pre-existing microvasculature. It occurs in physiological and pathological processes particularly in tumor growth and metastasis. α1, α2, α3, and α6 NC1 domains from type IV collagen were reported to inhibit tumor angiogenesis. We previously demonstrated that the α4 NC1 domain from type IV collagen, named Tetrastatin, inhibited tumor growth in a mouse melanoma model. The inhibitory activity was located in a 13 amino acid sequence named QS-13. In the present paper, we demonstrate that QS-13 decreases VEGF-induced-angiogenesis in vivo using the Matrigel plug model. Fluorescence molecular tomography allows the measurement of a 65% decrease in Matrigel plug angiogenesis following QS-13 administration. The results are confirmed by CD31 microvessel density analysis on Matrigel plug slices. QS-13 peptide decreases Human Umbilical Vein Endothelial Cells (HUVEC) migration and pseudotube formation in vitro. Relevant QS-13 conformations were obtained from molecular dynamics simulations and docking. A putative interaction of QS-13 with α 5 β 1 integrin was investigated. The interaction was confirmed by affinity chromatography, solid phase assay, and surface plasmon resonance. QS-13 binding site on α 5 β 1 integrin is located in close vicinity to the RGD binding site, as demonstrated by competition assays. Collectively, our results suggest that QS-13 exhibits a mighty anti-angiogenic activity that could be used in cancer treatment and other pathologies with excessive angiogenesis such as hemangioma, psoriasis or diabetes.

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Conformation-dependent binding of a Tetrastatin peptide to αvβ3 integrin decreases melanoma progression through FAK/PI3K/Akt pathway inhibition

Cited by 19 publications

References 38 publications

Tumor Microenvironment: Extracellular Matrix Alterations Influence Tumor Progression

Tumor Microenvironment: Extracellular Matrix Alterations Influence Tumor Progression

Cryptic collagen elements as signaling hubs in the regulation of tumor growth and metastasis

Angiogenesis Inhibition by a Short 13 Amino Acid Peptide Sequence of Tetrastatin, the α4(IV) NC1 Domain of Collagen IV

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