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

Mélanie Tichet (1) , Virginie Prod 'Homme (1) , Nina Fenouille (1) , Damien Ambrosetti (2) , Aude Mallavialle (1) , Michael Cerezo (1) , Mickaël Ohanna (1) , Stéphane Audebert (3) , Stéphane Rocchi (1) , Damien Giacchero (4) , Fériel Boukari (1, 4) , Maryline Allegra (1) , Jean-Claude Chambard (5) , Jean-Philippe Lacour (4) , Jean-François Michiels (2) , Jean-Paul Borg (3) , Marcel Deckert (1) , Sophie Tartare-Deckert (1)

1 C3M - Centre méditerranéen de médecine moléculaire
2 chu de nice, Hôpital Pasteur, Laboratoire Central d’Anatomo Pathologie
3 CRCM - Centre de Recherche en Cancérologie de Marseille
4 CHU de Nice, Hôpital Archet 2, Service de Dermatologie
5 IBV - Institut de Biologie Valrose

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.

Domaines: Sciences du Vivant [q-bio]

Mélanie Tichet, Virginie Prod 'Homme, Nina Fenouille, Damien Ambrosetti, Aude Mallavialle, et al.. Tumour-derived SPARC drives vascular permeability and extravasation through endothelial VCAM1 signalling to promote metastasis. Nature Communications, 2015, 6, pp.6993. ⟨10.1038/ncomms7993⟩. ⟨hal-01295443⟩