Regulated delivery of molecular cargo to invasive tumour-derived microvesicles

James W. Clancy, Alanna Sedgwick, Carine Rosse, Vandhana Muralidharan-Chari, Graca Raposo, Michael Method, Philippe Chavrier and Crislyn D’Souza-Schorey ()
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James W. Clancy: University of Notre Dame
Alanna Sedgwick: University of Notre Dame
Carine Rosse: Institut Curie, Centre de Recherche
Vandhana Muralidharan-Chari: University of Notre Dame
Graca Raposo: Institut Curie, Centre de Recherche
Michael Method: Northern Indiana Cancer Consortium, Michiana Hematology Oncology
Philippe Chavrier: Institut Curie, Centre de Recherche
Crislyn D’Souza-Schorey: University of Notre Dame

Nature Communications, 2015, vol. 6, issue 1, 1-11

Abstract: Abstract Cells release multiple, distinct forms of extracellular vesicles including structures known as microvesicles, which are known to alter the extracellular environment. Despite growing understanding of microvesicle biogenesis, function and contents, mechanisms regulating cargo delivery and enrichment remain largely unknown. Here we demonstrate that in amoeboid-like invasive tumour cell lines, the v-SNARE, VAMP3, regulates delivery of microvesicle cargo such as the membrane-type 1 matrix metalloprotease (MT1-MMP) to shedding microvesicles. MT1-MMP delivery to nascent microvesicles depends on the association of VAMP3 with the tetraspanin CD9 and facilitates the maintenance of amoeboid cell invasion. VAMP3-shRNA expression depletes shed vesicles of MT1-MMP and decreases cell invasiveness when embedded in cross-linked collagen matrices. Finally, we describe functionally similar microvesicles isolated from bodily fluids of ovarian cancer patients. Together these studies demonstrate the importance of microvesicle cargo sorting in matrix degradation and disease progression.

Date: 2015
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DOI: 10.1038/ncomms7919

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