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 (membrane-type 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.

A RAB5/RAB4 recycling circuitry induces a proteolytic invasive program and promotes tumor dissemination / E. Frittoli, A. Palamidessi, P. Marighetti, S. Confalonieri, F. Bianchi, C. Malinverno, G. Mazzarol, G. Viale, I. Martin-Padura, M. Garré, D. Parazzoli, V. Mattei, S. Cortellino, G. Bertalot, P.P. Di Fiore, G. Scita. - In: THE JOURNAL OF CELL BIOLOGY. - ISSN 0021-9525. - 206:2(2014 Jul 21), pp. 307-328. [10.1083/jcb.201403127]

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

C. Malinverno;G. Viale;P.P. Di Fiore
;
G. Scita
Ultimo
2014

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 (membrane-type 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.
Settore MED/04 - Patologia Generale
Settore MED/08 - Anatomia Patologica
21-lug-2014
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/237711
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