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

Mélanie Tichet, Virginie Prod’Homme, Nina Fenouille, Damien Ambrosetti, Aude Mallavialle, Michael Cerezo, Mickaël Ohanna, Stéphane Audebert, Stéphane Rocchi, Damien Giacchero, Fériel Boukari, Maryline Allegra, Jean-Claude Chambard, Jean-Philippe Lacour, Jean-François Michiels, Jean-Paul Borg, Marcel Deckert and Sophie Tartare-Deckert ()
Additional contact information
Mélanie Tichet: INSERM, U1065, Microenvironnement, Signalisation et Cancer, Centre Méditerranéen de Médecine Moléculaire (C3M), 151 Route de Saint-Antoine de Ginestière
Virginie Prod’Homme: INSERM, U1065, Microenvironnement, Signalisation et Cancer, Centre Méditerranéen de Médecine Moléculaire (C3M), 151 Route de Saint-Antoine de Ginestière
Nina Fenouille: INSERM, U1065, Microenvironnement, Signalisation et Cancer, Centre Méditerranéen de Médecine Moléculaire (C3M), 151 Route de Saint-Antoine de Ginestière
Damien Ambrosetti: Université de Nice Sophia Antipolis, Faculté de Médecine
Aude Mallavialle: INSERM, U1065, Microenvironnement, Signalisation et Cancer, Centre Méditerranéen de Médecine Moléculaire (C3M), 151 Route de Saint-Antoine de Ginestière
Michael Cerezo: Université de Nice Sophia Antipolis, Faculté de Médecine
Mickaël Ohanna: Université de Nice Sophia Antipolis, Faculté de Médecine
Stéphane Audebert: CRCM, INSERM U1068, Institut Paoli-Calmettes, Aix-Marseille Université, UM105; CNRS UMR7258
Stéphane Rocchi: Université de Nice Sophia Antipolis, Faculté de Médecine
Damien Giacchero: Université de Nice Sophia Antipolis, Faculté de Médecine
Fériel Boukari: INSERM, U1065, Microenvironnement, Signalisation et Cancer, Centre Méditerranéen de Médecine Moléculaire (C3M), 151 Route de Saint-Antoine de Ginestière
Maryline Allegra: Université de Nice Sophia Antipolis, Faculté de Médecine
Jean-Claude Chambard: Université de Nice Sophia Antipolis, Faculté de Médecine
Jean-Philippe Lacour: Université de Nice Sophia Antipolis, Faculté de Médecine
Jean-François Michiels: Université de Nice Sophia Antipolis, Faculté de Médecine
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
Sophie Tartare-Deckert: INSERM, U1065, Microenvironnement, Signalisation et Cancer, Centre Méditerranéen de Médecine Moléculaire (C3M), 151 Route de Saint-Antoine de Ginestière

Nature Communications, 2015, vol. 6, issue 1, 1-15

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms7993

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