title: NHERF1 acts as a molecular switch to program metastatic behavior and organotropism via its PDZ domains.
abstract: Metastatic cells are highly plastic for differential expression of tumor phenotype hallmarks and metastatic organotropism. The signaling proteins orchestrating the shift of one cell phenotype and organ pattern to another are little known. Na(+)/H(+) exchanger regulatory factor (NHERF1) is a molecular pathway organizer, PDZ-domain protein that recruits membrane, cytoplasmic, and cytoskeletal signaling proteins into functional complexes. To gain insight into the role of NHERF1 in metastatic progression, we stably transfected a metastatic breast cell line, MDA-MB-231, with an empty vector, with wild-type NHERF1, or with NHERF1 mutated in either the PDZ1- or PDZ2-binding domains to block their binding activities. We observed that NHERF1 differentially regulates the expression of two phenotypic programs through its PDZ domains, and these programs form the mechanistic basis for metastatic organotropism. The PDZ2 domain promotes visceral metastases via increased invadopodia-dependent invasion and anchorage-independent growth, as well as by inhibition of apoptosis, whereas the PDZ1 domain promotes bone metastases by stimulating podosome nucleation, motility, neoangiogenesis, vasculogenic mimicry, and osteoclastogenesis in the absence of increased growth or invasion. Collectively, these findings identify NHERF1 as an important signaling nexus for coordinating cell structure with metastatic behavior and identifies the "mesenchymal-to-vasculogenic" phenotypic transition as an essential step in metastatic progression.
authors.affiliation: Department of Bioscience, Biotechnology and Pharmacological Sciences, University of Bari, Bari, Italy. r.cardone@biologia.uniba.it
authors.forename: Rosa Angela
authors.initials: RA
authors.lastname: Cardone
authors.forename: Maria Raffaella
authors.initials: MR
authors.lastname: Greco
authors.forename: Mattia
authors.initials: M
authors.lastname: Capulli
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Weinman
authors.forename: Giovanni
authors.initials: G
authors.lastname: Busco
authors.forename: Antonia
authors.initials: A
authors.lastname: Bellizzi
authors.forename: Valeria
authors.initials: V
authors.lastname: Casavola
authors.forename: Ester
authors.initials: E
authors.lastname: Antelmi
authors.forename: Barbara
authors.initials: B
authors.lastname: Ambruosi
authors.forename: Maria Elena
authors.initials: ME
authors.lastname: Dell'Aquila
authors.forename: Angelo
authors.initials: A
authors.lastname: Paradiso
authors.forename: Anna
authors.initials: A
authors.lastname: Teti
authors.forename: Nadia
authors.initials: N
authors.lastname: Rucci
authors.forename: Stephan Joel
authors.initials: SJ
authors.lastname: Reshkin
mesh_terms: D000818:Animals; D017209:Apoptosis; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008954:Models, Biological; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology; D054731:PDZ Domains; D010750:Phosphoproteins / Q000737:chemistry* / Q000378:metabolism*; D011554:Pseudopodia / Q000378:metabolism; D017923:Sodium-Hydrogen Exchangers / Q000737:chemistry* / Q000378:metabolism*; D013329:Structure-Activity Relationship; D018523:Tropism; D023041:Xenograft Model Antitumor Assays
chemical_list: D010750:Phosphoproteins; D017923:Sodium-Hydrogen Exchangers; C093376:sodium-hydrogen exchanger regulatory factor