title: A RAB5/RAB4 recycling circuitry induces a proteolytic invasive program and promotes tumor dissemination.
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.
authors: Fondazione Istituto FIRC di Oncologia Molecolare (IFOM), 20139 Milan, Italy.
authors: Emanuela
authors: E
authors: Frittoli
authors: Fondazione Istituto FIRC di Oncologia Molecolare (IFOM), 20139 Milan, Italy.
authors: Andrea
authors: A
authors: Palamidessi
authors: Fondazione Istituto FIRC di Oncologia Molecolare (IFOM), 20139 Milan, Italy.
authors: Paola
authors: P
authors: Marighetti
authors: Fondazione Istituto FIRC di Oncologia Molecolare (IFOM), 20139 Milan, Italy Dipartimento di Oncologia Sperimentale, Istituto Europeo di Oncologia, 20141 Milan, Italy.
authors: Stefano
authors: S
authors: Confalonieri
authors: Dipartimento di Oncologia Sperimentale, Istituto Europeo di Oncologia, 20141 Milan, Italy.
authors: Fabrizio
authors: F
authors: Bianchi
authors: Fondazione Istituto FIRC di Oncologia Molecolare (IFOM), 20139 Milan, Italy.
authors: Chiara
authors: C
authors: Malinverno
authors: Dipartimento di Oncologia Sperimentale, Istituto Europeo di Oncologia, 20141 Milan, Italy.
authors: Giovanni
authors: G
authors: Mazzarol
authors: Dipartimento di Oncologia Sperimentale, Istituto Europeo di Oncologia, 20141 Milan, Italy.
authors: Giuseppe
authors: G
authors: Viale
authors: Dipartimento di Oncologia Sperimentale, Istituto Europeo di Oncologia, 20141 Milan, Italy.
authors: Ines
authors: I
authors: Martin-Padura
authors: Fondazione Istituto FIRC di Oncologia Molecolare (IFOM), 20139 Milan, Italy.
authors: Massimilliano
authors: M
authors: Garré
authors: Fondazione Istituto FIRC di Oncologia Molecolare (IFOM), 20139 Milan, Italy.
authors: Dario
authors: D
authors: Parazzoli
authors: Dipartimento di Oncologia Sperimentale, Istituto Europeo di Oncologia, 20141 Milan, Italy.
authors: Valentina
authors: V
authors: Mattei
authors: Fondazione Istituto FIRC di Oncologia Molecolare (IFOM), 20139 Milan, Italy.
authors: Salvatore
authors: S
authors: Cortellino
authors: Dipartimento di Oncologia Sperimentale, Istituto Europeo di Oncologia, 20141 Milan, Italy.
authors: Giovanni
authors: G
authors: Bertalot
authors: Fondazione Istituto FIRC di Oncologia Molecolare (IFOM), 20139 Milan, Italy Dipartimento di Oncologia Sperimentale, Istituto Europeo di Oncologia, 20141 Milan, Italy Dipartimento di Scienze della Salute, Università degli Studi di Milano, 20122 Milan, Italy pierpaolo.difiore@ifom.eu giorgio.scita@ifom.eu.
authors: Pier Paolo
authors: PP
authors: Di Fiore
authors: Fondazione Istituto FIRC di Oncologia Molecolare (IFOM), 20139 Milan, Italy Dipartimento di Scienze della Salute, Università degli Studi di Milano, 20122 Milan, Italy pierpaolo.difiore@ifom.eu giorgio.scita@ifom.eu.
authors: Giorgio
authors: G
authors: Scita
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D018450:Disease Progression; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D009361:Neoplasm Invasiveness / Q000235:genetics; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000473:pathology; D059748:Proteolysis; D014183:Transplantation, Heterologous; D020696:rab5 GTP-Binding Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*
chemical_list: D020696:rab5 GTP-Binding Proteins