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Tumour-derived SPARC drives vascular permeability and extravasation through endothelial VCAM1 signalling to promote metastasis

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  • Mélanie Tichet

    (INSERM, U1065, Microenvironnement, Signalisation et Cancer, Centre Méditerranéen de Médecine Moléculaire (C3M), 151 Route de Saint-Antoine de Ginestière
    Université de Nice Sophia Antipolis, Faculté de Médecine)

  • Virginie Prod’Homme

    (INSERM, U1065, Microenvironnement, Signalisation et Cancer, Centre Méditerranéen de Médecine Moléculaire (C3M), 151 Route de Saint-Antoine de Ginestière
    Université de Nice Sophia Antipolis, Faculté de Médecine)

  • Nina Fenouille

    (INSERM, U1065, Microenvironnement, Signalisation et Cancer, Centre Méditerranéen de Médecine Moléculaire (C3M), 151 Route de Saint-Antoine de Ginestière
    Université de Nice Sophia Antipolis, Faculté de Médecine)

  • Damien Ambrosetti

    (Université de Nice Sophia Antipolis, Faculté de Médecine
    Centre Hospitalier Universitaire (CHU) de Nice, Hôpital Pasteur, Laboratoire Central d'Anatomo Pathologie)

  • Aude Mallavialle

    (INSERM, U1065, Microenvironnement, Signalisation et Cancer, Centre Méditerranéen de Médecine Moléculaire (C3M), 151 Route de Saint-Antoine de Ginestière
    Université de Nice Sophia Antipolis, Faculté de Médecine)

  • Michael Cerezo

    (Université de Nice Sophia Antipolis, Faculté de Médecine
    INSERM, U1065, Biologie et Pathologies des Mélanocytes, C3M, 151 Route de Saint-Antoine de Ginestière)

  • Mickaël Ohanna

    (Université de Nice Sophia Antipolis, Faculté de Médecine
    INSERM, U1065, Biologie et Pathologies des Mélanocytes, C3M, 151 Route de Saint-Antoine de Ginestière)

  • Stéphane Audebert

    (CRCM, INSERM U1068, Institut Paoli-Calmettes, Aix-Marseille Université, UM105; CNRS UMR7258)

  • Stéphane Rocchi

    (Université de Nice Sophia Antipolis, Faculté de Médecine
    INSERM, U1065, Biologie et Pathologies des Mélanocytes, C3M, 151 Route de Saint-Antoine de Ginestière)

  • Damien Giacchero

    (Université de Nice Sophia Antipolis, Faculté de Médecine
    CHU de Nice, Hôpital Archet 2, Service de Dermatologie)

  • Fériel Boukari

    (INSERM, U1065, Microenvironnement, Signalisation et Cancer, Centre Méditerranéen de Médecine Moléculaire (C3M), 151 Route de Saint-Antoine de Ginestière
    Université de Nice Sophia Antipolis, Faculté de Médecine
    CHU de Nice, Hôpital Archet 2, Service de Dermatologie)

  • Maryline Allegra

    (Université de Nice Sophia Antipolis, Faculté de Médecine
    INSERM, U1065, Biologie et Pathologies des Mélanocytes, C3M, 151 Route de Saint-Antoine de Ginestière)

  • Jean-Claude Chambard

    (Université de Nice Sophia Antipolis, Faculté de Médecine
    INSERM, U1091, CNRS, UMR 7277, iBV, Faculté des Sciences, Parc Valrose)

  • Jean-Philippe Lacour

    (Université de Nice Sophia Antipolis, Faculté de Médecine
    CHU de Nice, Hôpital Archet 2, Service de Dermatologie)

  • Jean-François Michiels

    (Université de Nice Sophia Antipolis, Faculté de Médecine
    Centre Hospitalier Universitaire (CHU) de Nice, Hôpital Pasteur, Laboratoire Central d'Anatomo Pathologie)

  • Jean-Paul Borg

    (CRCM, INSERM U1068, Institut Paoli-Calmettes, Aix-Marseille Université, UM105; CNRS UMR7258)

  • Marcel Deckert

    (INSERM, U1065, Microenvironnement, Signalisation et Cancer, Centre Méditerranéen de Médecine Moléculaire (C3M), 151 Route de Saint-Antoine de Ginestière
    Université de Nice Sophia Antipolis, Faculté de Médecine)

  • Sophie Tartare-Deckert

    (INSERM, U1065, Microenvironnement, Signalisation et Cancer, Centre Méditerranéen de Médecine Moléculaire (C3M), 151 Route de Saint-Antoine de Ginestière
    Université de Nice Sophia Antipolis, Faculté de Médecine)

Abstract

Disruption of the endothelial barrier by tumour-derived secreted factors is a critical step in cancer cell extravasation and metastasis. Here, by comparative proteomic analysis of melanoma secretomes, we identify the matricellular protein SPARC as a novel tumour-derived vascular permeability factor. SPARC deficiency abrogates tumour-initiated permeability of lung capillaries and prevents extravasation, whereas SPARC overexpression enhances vascular leakiness, extravasation and lung metastasis. SPARC-induced paracellular permeability is dependent on the endothelial VCAM1 receptor and p38 MAPK signalling. Blocking VCAM1 impedes melanoma-induced endothelial permeability and extravasation. The clinical relevance of our findings is highlighted by high levels of SPARC detected in tumour from human pulmonary melanoma lesions. Our study establishes tumour-produced SPARC and VCAM1 as regulators of cancer extravasation, revealing a novel targetable interaction for prevention of metastasis.

Suggested Citation

  • Mélanie Tichet & Virginie Prod’Homme & Nina Fenouille & Damien Ambrosetti & Aude Mallavialle & Michael Cerezo & Mickaël Ohanna & Stéphane Audebert & Stéphane Rocchi & Damien Giacchero & Fériel Boukari, 2015. "Tumour-derived SPARC drives vascular permeability and extravasation through endothelial VCAM1 signalling to promote metastasis," Nature Communications, Nature, vol. 6(1), pages 1-15, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms7993
    DOI: 10.1038/ncomms7993
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