title: Targeting Lyn regulates Snail family shuttling and inhibits metastasis.
abstract: The acquisition of an invasive phenotype by epithelial cells occurs through a loss of cellular adhesion and polarity, heralding a multistep process that leads to metastatic dissemination. Since its characterization in 1995, epithelial-mesenchymal transition (EMT) has been closely linked to the metastatic process. As a defining aspect of EMT, loss of cell adhesion through downregulation of E-cadherin is carried out by several transcriptional repressors; key among them the SNAI family of transcription factors. Here we identify for the first time that Lyn kinase functions as a key modulator of SNAI family protein localization and stability through control of the Vav-Rac1-PAK1 (Vav-Rac1-p21-activated kinase) pathway. Accordingly, targeting Lyn in vitro reduces EMT and in vivo reduces metastasis of primary tumors. We also demonstrate the clinical relevance of targeting Lyn as a key player controlling EMT; patient samples across many cancers revealed a strong negative correlation between Lyn and E-cadherin, and high Lyn expression in metastatic tumors as well as metastasis-prone primary tumors. This work reveals a novel pancancer mechanism of Lyn-dependent control of EMT and further underscores the role of this kinase in tumor progression.
authors.affiliation: Department of Urology, Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada.|Faculty of Medicine, Department of Urologic Science, University of British Columbia, Vancouver, BC, Canada.
authors.forename: D
authors.initials: D
authors.lastname: Thaper
authors.affiliation: Department of Urology, Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada.|Faculty of Medicine, Department of Urologic Science, University of British Columbia, Vancouver, BC, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Vahid
authors.affiliation: Department of Urology, Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada.|Faculty of Medicine, Department of Urologic Science, University of British Columbia, Vancouver, BC, Canada.
authors.forename: K M
authors.initials: KM
authors.lastname: Nip
authors.affiliation: Department of Urology, Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada.
authors.forename: I
authors.initials: I
authors.lastname: Moskalev
authors.affiliation: Faculty of Medicine, Department Ophthalmology and Visual Sciences, University of British Columbia, Vancouver, BC, Canada.
authors.forename: X
authors.initials: X
authors.lastname: Shan
authors.affiliation: Department of Urology, Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Frees
authors.affiliation: Faculty of Science, Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada.
authors.forename: M E
authors.initials: ME
authors.lastname: Roberts
authors.affiliation: Department of Urology, Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada.
authors.forename: K
authors.initials: K
authors.lastname: Ketola
authors.affiliation: Faculty of Science, Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada.
authors.forename: K W
authors.initials: KW
authors.lastname: Harder
authors.affiliation: Faculty of Medicine, Department Ophthalmology and Visual Sciences, University of British Columbia, Vancouver, BC, Canada.
authors.forename: C
authors.initials: C
authors.lastname: Gregory-Evans
authors.affiliation: Department of Urology, Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada.
authors.forename: J L
authors.initials: JL
authors.lastname: Bishop
authors.affiliation: Department of Urology, Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada.|Faculty of Medicine, Department of Urologic Science, University of British Columbia, Vancouver, BC, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Zoubeidi
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D058990:Molecular Targeted Therapy; D009362:Neoplasm Metastasis / Q000235:genetics / Q000517:prevention & control*; D009369:Neoplasms / Q000235:genetics / Q000473:pathology; D021381:Protein Transport / Q000187:drug effects / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology*; D000071250:Snail Family Transcription Factors / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000235:genetics*
chemical_list: D034741:RNA, Small Interfering; D000071250:Snail Family Transcription Factors; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases