A RAB5/RAB4 recycling circuitry induces a proteolytic invasive program and promotes tumor dissemination

• DOI: 10.1083/jcb.201403127
• Publication Date: 2014-07-21T22:53:31Z
• Authors: Emanuela Frittoli; Andrea Palamidessi; Paola Marighetti; Stefano Confalonieri; Fabrizio Bianchi; Chiara Malinverno; Giovanni Mazzarol; Giuseppe Viale; Ines Martin-Padura; Massimilliano Garré; Dario Parazzoli; Valentina Mattei; Salvatore Cortellino; Giovanni Bertalot; Pier Paolo Di Fiore; Giorgio Scita
• Keywords: 0301 basic medicine; Transplantation, Heterologous; Breast Neoplasms; Extracellular Matrix; Gene Expression Regulation, Neoplastic; Mice; 03 medical and health sciences; Cell Line, Tumor; Proteolysis; Disease Progression; Animals; Humans; Female; Neoplasm Invasiveness; Neoplasm Recurrence, Local; Research Articles; rab5 GTP-Binding Proteins

The mechanisms by which tumor cells metastasize and the role of endocytic proteins in this process are not well understood. We report that overexpression GTPase RAB5A, a master regulator endocytosis, is predictive aggressive behavior metastatic ability human breast cancers. RAB5A necessary sufficient to promote local invasion distant dissemination various mammary nonmammary cell lines, prometastatic associated with increased intratumoral motility. Specifically, for formation invadosomes, membrane protrusions specialized extracellular matrix (ECM) degradation. promotes RAB4- RABENOSYN-5–dependent endo/exocytic cycles (EECs) critical cargos (membrane-type 1 metalloprotease [MT1-MMP] β3 integrin) required invadosome response motogenic stimuli. This trafficking circuitry spatially localized hepatocyte growth factor (HGF)/MET signaling drives invasive, proteolysis-dependent chemotaxis vitro conversion ductal carcinoma situ invasive vivo. Thus, RAB5A/RAB4 EECs controlling proteolytic, mesenchymal program.