Oral communication, CS19 / C88

Official XXIst International Pigment Cell Conference website - 21-24 Sept 2011, Bordeaux - France | updated: September 04 2011

SPARC acts as a VCAM-1 ligand to mediate melanoma extravasation and distant metastasis

SPEAKER M. Tichet #whois submiter ?
AUTHOR(s) M. Tichet, N. Fenouille, P. Abbe, S. Rocchi, M. Allegra, J.-C. Chambard, M. Vivinus, J.-P. Lacour, R. Ballotti, M. Deckert, S. Tartare-Deckert

A hallmark feature of melanoma is its metastatic propensity. Metastasis occurs by a complex process whereby tumor cells dissociate from their primary site of growth, invade surrounding tissues, intravasate into a blood vessel, adhere to and extravasate from the vessel, and form a new tumor at secondary site. SPARC is a secreted matricellular protein, which is highly produced by melanoma cells. Clinical studies have reported that elevated SPARC is associated with melanoma patients with poor survival and occurrence of distant metastases. Mechanistically, tumor cell-autonomous SPARC signaling promotes invasive abilities and favors melanoma growth by inhibiting p53 tumor suppression function. Although SPARC has a significant role in invasion and cell survival, its contribution to later stages of the metastatic cascade such as tumor-endothelial cell interactions and extravasation remains unexplored. By modeling in vitro the extravasation process between metastatic melanoma from short-term cultures or cell lines and primary vascular endothelial cells, we show that melanoma cell–derived SPARC is dispensable for adhesion of tumor cells to TNF-alpha-activated endothelial cell monolayers but required for subsequent transendothelial migration. SPARC-induced transendothelial migration is partially dependent on its binding to vascular adhesion molecule (VCAM-1) expressed on inflamed endothelial cells. Melanoma cell SPARC activates Src family kinases and p38 MAPK in endothelial cells and promotes intercellular gaps permissive for tumor cell diapedesis. Importantly, SPARC-mediated melanoma transmigration does not require the p53 regulatory function of SPARC. Using fluorescence and bioluminescence imaging, we also show that knockdown of SPARC leads to a dramatic decrease in short-term and long-term colonization of the lungs by melanoma cells. Together, our studies reveal that tumor cell SPARC is emerging as a multifunctional mediator of metastatic development contributing both to local invasion and lung extravasation, which provide a rationale and mechanistic basis for targeting SPARC to inhibit melanoma metastases.



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Université de Bordeaux 2 & Conseil Régional Aquitaine