title: RAB2A controls MT1-MMP endocytic and E-cadherin polarized Golgi trafficking to promote invasive breast cancer programs.
abstract: The mechanisms of tumor cell dissemination and the contribution of membrane trafficking in this process are poorly understood. Through a functional siRNA screening of human RAB GTPases, we found that RAB2A, a protein essential for ER-to-Golgi transport, is critical in promoting proteolytic activity and 3D invasiveness of breast cancer (BC) cell lines. Remarkably, RAB2A is amplified and elevated in human BC and is a powerful and independent predictor of disease recurrence in BC patients. Mechanistically, RAB2A acts at two independent trafficking steps. Firstly, by interacting with VPS39, a key component of the late endosomal HOPS complex, it controls post-endocytic trafficking of membrane-bound MT1-MMP, an essential metalloprotease for matrix remodeling and invasion. Secondly, it further regulates Golgi transport of E-cadherin, ultimately controlling junctional stability, cell compaction, and tumor invasiveness. Thus, RAB2A is a novel trafficking determinant essential for regulation of a mesenchymal invasive program of BC dissemination.
authors.affiliation: IFOM, the FIRC Institute of Molecular Oncology, Milan, Italy.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Kajiho
authors.affiliation: IFOM, the FIRC Institute of Molecular Oncology, Milan, Italy Department of Pediatrics, Graduate School of Medicine The University of Tokyo, Tokyo, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Kajiho
authors.affiliation: IFOM, the FIRC Institute of Molecular Oncology, Milan, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Frittoli
authors.affiliation: IFOM, the FIRC Institute of Molecular Oncology, Milan, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Confalonieri
authors.affiliation: Molecular Medicine Program, European Institute of Oncology, Milan, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Bertalot
authors.affiliation: Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Milan, Italy Department of Pathology, European Institute of Oncology, Milan, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Viale
authors.affiliation: IFOM, the FIRC Institute of Molecular Oncology, Milan, Italy Molecular Medicine Program, European Institute of Oncology, Milan, Italy Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Milan, Italy.
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Di Fiore
authors.affiliation: IFOM, the FIRC Institute of Molecular Oncology, Milan, Italy.
authors.forename: Amanda
authors.initials: A
authors.lastname: Oldani
authors.affiliation: IFOM, the FIRC Institute of Molecular Oncology, Milan, Italy.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Garre
authors.affiliation: IFOM, the FIRC Institute of Molecular Oncology, Milan, Italy.
authors.forename: Galina V
authors.initials: GV
authors.lastname: Beznoussenko
authors.affiliation: IFOM, the FIRC Institute of Molecular Oncology, Milan, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Palamidessi
authors.affiliation: IFOM, the FIRC Institute of Molecular Oncology, Milan, Italy Molecular Medicine Program, European Institute of Oncology, Milan, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Vecchi
authors.affiliation: Institut Curie, PSL Research University, Paris Cedex 05, France Centre National de la Recherche Scientifique, Unité Mixte de Recherche 144 CNRS UMR 144, Paris Cedex 05, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Chavrier
authors.affiliation: Institut Curie, PSL Research University, Paris Cedex 05, France Centre National de la Recherche Scientifique, Unité Mixte de Recherche 144 CNRS UMR 144, Paris Cedex 05, France.
authors.forename: Frank
authors.identifier: 0000-0002-9129-9401
authors.initials: F
authors.lastname: Perez
authors.affiliation: IFOM, the FIRC Institute of Molecular Oncology, Milan, Italy Molecular Medicine Program, European Institute of Oncology, Milan, Italy Giorgio.Scita@ifom.eu.
authors.forename: Giorgio
authors.identifier: 0000-0001-7984-1889
authors.initials: G
authors.lastname: Scita
mesh_terms: D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D015820:Cadherins / Q000378:metabolism*; D045744:Cell Line, Tumor; D011992:Endosomes / Q000378:metabolism; D005089:Exocytosis; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D020868:Gene Silencing; D006056:Golgi Apparatus / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D011379:Prognosis; D021381:Protein Transport; D059748:Proteolysis; D012008:Recurrence; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; D015820:Cadherins; C476884:HOPX protein, human; D018398:Homeodomain Proteins; D025521:Tumor Suppressor Proteins; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14; D020691:rab GTP-Binding Proteins
keywords: RAB GTPases; RAB2A; cancer migration and invasion; membrane trafficking