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 language | English |
|---|---|
| Pages (from-to) | 307-328 |
| Number of pages | 22 |
| Journal | Journal of Cell Biology |
| Volume | 206 |
| Issue number | 2 |
| DOIs | |
| Publication status | Published - 2014 |
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ASJC Scopus subject areas
- Cell Biology
Cite this
A RAB5/RAB4 recycling circuitry induces a proteolytic invasive program and promotes tumor dissemination. / Frittoli, Emanuela; Palamidessi, Andrea; Marighetti, Paola; Confalonieri, Stefano; Bianchi, Fabrizio; Malinverno, Chiara; Mazzaro, Giovanni; Viale, Giuseppe; Martin-Padura, Giuseppe; Garré, Massimilliano; Parazzoli, Dario; Mattei, Valentina; Cortellino, Salvatore; Bertalot, Giovanni; Di Fiore, Pier Paolo; Scita, Giorgio.
In: Journal of Cell Biology, Vol. 206, No. 2, 2014, p. 307-328.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - A RAB5/RAB4 recycling circuitry induces a proteolytic invasive program and promotes tumor dissemination
AU - Frittoli, Emanuela
AU - Palamidessi, Andrea
AU - Marighetti, Paola
AU - Confalonieri, Stefano
AU - Bianchi, Fabrizio
AU - Malinverno, Chiara
AU - Mazzaro, Giovanni
AU - Viale, Giuseppe
AU - Martin-Padura, Giuseppe
AU - Garré, Massimilliano
AU - Parazzoli, Dario
AU - Mattei, Valentina
AU - Cortellino, Salvatore
AU - Bertalot, Giovanni
AU - Di Fiore, Pier Paolo
AU - Scita, Giorgio
PY - 2014
Y1 - 2014
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84904701296&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84904701296&partnerID=8YFLogxK
U2 - 10.1083/jcb.201403127
DO - 10.1083/jcb.201403127
M3 - Article
C2 - 25049275
AN - SCOPUS:84904701296
VL - 206
SP - 307
EP - 328
JO - Journal of Cell Biology
JF - Journal of Cell Biology
SN - 0021-9525
IS - 2
ER -