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

Emanuela Frittoli, Andrea Palamidessi, Paola Marighetti, Stefano Confalonieri, Fabrizio Bianchi, Chiara Malinverno, Giovanni Mazzaro, Giuseppe Viale, Giuseppe Martin-Padura, Massimilliano Garré, Dario Parazzoli, Valentina Mattei, Salvatore Cortellino, Giovanni Bertalot, Pier Paolo Di Fiore, Giorgio Scita

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Abstract

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

Original languageEnglish
Pages (from-to)307-328
Number of pages22
JournalJournal of Cell Biology
Volume206
Issue number2
DOIs
Publication statusPublished - 1 Jan 2014
Externally publishedYes

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ASJC Scopus subject areas

  • Cell Biology

Cite this

Frittoli, E., Palamidessi, A., Marighetti, P., Confalonieri, S., Bianchi, F., Malinverno, C., Mazzaro, G., Viale, G., Martin-Padura, G., Garré, M., Parazzoli, D., Mattei, V., Cortellino, S., Bertalot, G., Di Fiore, P. P., & Scita, G. (2014). A RAB5/RAB4 recycling circuitry induces a proteolytic invasive program and promotes tumor dissemination. Journal of Cell Biology, 206(2), 307-328. https://doi.org/10.1083/jcb.201403127