title: An integrin-linked machinery of cytoskeletal regulation that enables experimental tumor initiation and metastatic colonization.
abstract: Recently extravasated metastatic cancer cells use the Rif/mDia2 actin-nucleating/polymerizing machinery in order to extend integrin β1-containing, filopodium-like protrusions (FLPs), which enable them to interact productively with the surrounding extracellular matrix; this process governs the initial proliferation of these cancer cells. Here, we identify the signaling pathway governing FLP lifetime, which involves integrin-linked kinase (ILK) and β-parvin, two integrin:actin-bridging proteins that block cofilin-mediated actin-filament severing. Notably, the combined actions of Rif/mDia2 and ILK/β-parvin/cofilin pathways on FLPs are required not only for metastatic outgrowth but also for primary tumor formation following experimental implantation. This provides one mechanistic explanation for how the epithelial-mesenchymal transition (EMT) program imparts tumor-initiating powers to carcinoma cells, since it enhances FLP formation through the activation of ILK/β-parvin/cofilin pathway.
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; MIT Ludwig Center for Molecular Oncology, Cambridge, MA 02139, USA.
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Shibue
authors.forename: Mary W
authors.initials: MW
authors.lastname: Brooks
authors.forename: Robert A
authors.initials: RA
authors.lastname: Weinberg
mesh_terms: D000185:Actinin / Q000378:metabolism*; D000199:Actins / Q000378:metabolism; D000818:Animals; D002277:Carcinoma / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D003599:Cytoskeleton / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000166:cytology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D000099200:Scaffold Protein ILK
chemical_list: D000185:Actinin; D000199:Actins; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger; D000099200:Scaffold Protein ILK; C486591:PARVB protein, human
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