title: Rewiring of an epithelial differentiation factor, miR-203, to inhibit human squamous cell carcinoma metastasis.
abstract: Metastatic colonization of distant organs underpins the majority of human-cancer-related deaths, including deaths from head and neck squamous cell carcinoma (HNSCC). We report that miR-203, a miRNA that triggers differentiation in multilayered epithelia, inhibits multiple postextravasation events during HNSCC lung metastasis. Inducible reactivation of miR-203 in already established lung metastases reduces the overall metastatic burden. Using an integrated approach, we reveal that miR-203 inhibits metastasis independently of its effects on differentiation. In vivo genetic reconstitution experiments show that miR-203 inhibits lung metastasis by suppressing the prometastatic activities of three factors involved in cytoskeletal dynamics (LASP1), extracellular matrix remodeling (SPARC), and cell metabolism (NUAK1). Expression of miR-203 and its downstream effectors correlates with HNSCC overall survival outcomes, indicating the therapeutic potential of targeting this signaling axis.
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK; Centre for Stem Cells and Regenerative Medicine, King's College London, 28(th) Floor, Tower Wing, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK.
authors.forename: Nathan
authors.initials: N
authors.lastname: Benaich
authors.affiliation: Centre for Stem Cells and Regenerative Medicine, King's College London, 28(th) Floor, Tower Wing, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK.
authors.forename: Samuel
authors.initials: S
authors.lastname: Woodhouse
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Goldie
authors.affiliation: Centre for Stem Cells and Regenerative Medicine, King's College London, 28(th) Floor, Tower Wing, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK.
authors.forename: Ajay
authors.initials: A
authors.lastname: Mishra
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK; Clinic of Dermatology and Venereology, Otto-von-Guericke University, Magdeburg, Leipziger Strasse 44, 39120 Magdeburg, Germany.
authors.forename: Sven R
authors.initials: SR
authors.lastname: Quist
authors.affiliation: Centre for Stem Cells and Regenerative Medicine, King's College London, 28(th) Floor, Tower Wing, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK. Electronic address: fiona.watt@kcl.ac.uk.
authors.forename: Fiona M
authors.initials: FM
authors.lastname: Watt
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D002454:Cell Differentiation / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D003598:Cytoskeletal Proteins / Q000037:antagonists & inhibitors; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D064593:Heterografts; D006801:Humans; D060588:LIM Domain Proteins / Q000037:antagonists & inhibitors; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control* / Q000556:secondary*; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D009362:Neoplasm Metastasis; D015676:Osteonectin / Q000037:antagonists & inhibitors; D011379:Prognosis; D011494:Protein Kinases; D012097:Repressor Proteins / Q000037:antagonists & inhibitors; D015398:Signal Transduction; D000077195:Squamous Cell Carcinoma of Head and Neck
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; C096353:LASP1 protein, human; D060588:LIM Domain Proteins; C546703:MIRN203 microRNA, human; D035683:MicroRNAs; D015676:Osteonectin; D012097:Repressor Proteins; C577241:SPARC protein, human; D011494:Protein Kinases; C470845:NUAK1 protein, human