Targeting Lyn regulates Snail family shuttling and inhibits metastasis

• Published in: Oncogene Vol. 36; no. 28; pp. 3964 - 3975
• Main Authors: Thaper, D, Vahid, S, Nip, K M, Moskalev, I, Shan, X, Frees, S, Roberts, M E, Ketola, K, Harder, K W, Gregory-Evans, C, Bishop, J L, Zoubeidi, A
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 13.07.2017; Nature Publishing Group
• Subjects: 13/106; 13/95; 14/19; 38/70; 45/29; 59/5; 631/67/322; 631/80/84; 64/116; 64/60; Animals; Apoptosis; Cancer metastasis; Cell adhesion; Cell adhesion & migration; Cell Biology; Cell Line, Tumor; E-cadherin; Epithelial cells; Epithelial-Mesenchymal Transition - drug effects; Epithelial-Mesenchymal Transition - genetics; Gene Expression Regulation, Neoplastic - drug effects; Genetic aspects; Genotype & phenotype; GTP-binding protein; Health aspects; Human Genetics; Humans; Internal Medicine; Kinases; Localization; Lyn protein; Medicine; Medicine & Public Health; Mesenchyme; Metastases; Metastasis; Mice; Molecular Targeted Therapy; Neoplasm Metastasis - genetics; Neoplasm Metastasis - prevention & control; Neoplasms - genetics; Neoplasms - pathology; Oncology; original-article; p21-activated kinase; Phenotypes; Polarity; Protein Transport - drug effects; Protein Transport - genetics; Rac1 protein; Repressors; Risk factors; RNA, Small Interfering - pharmacology; Snail Family Transcription Factors - metabolism; src-Family Kinases - antagonists & inhibitors; src-Family Kinases - genetics; Transcription factors; Tumors; Xenograft Model Antitumor Assays
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2017.5

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.