title: TGF-β-Induced Transcription Sustains Amoeboid Melanoma Migration and Dissemination.
abstract: Cell migration underlies metastatic dissemination of cancer cells, and fast "amoeboid" migration in the invasive fronts of tumors is controlled by high levels of actomyosin contractility. How amoeboid migration is regulated by extracellular signals and sustained over time by transcriptional changes is not fully understood. Transforming growth factor β (TGF-β) is well known to promote epithelial-to-mesenchymal transition (EMT) and contribute to metastasis, but melanocytes are neural crest derivatives that have undergone EMT during embryonic development. Surprisingly, we find that in melanoma, TGF-β promotes amoeboid features such as cell rounding, membrane blebbing, high levels of contractility, and increased invasion. Using genome-wide transcriptomics, we find that amoeboid melanoma cells are enriched in a TGF-β-driven signature. We observe that downstream of TGF-β, SMAD2 and its adaptor CITED1 control amoeboid behavior by regulating the expression of key genes that activate contractile forces. Moreover, CITED1 is highly upregulated during melanoma progression, and its high expression is associated with poor prognosis. CITED1 is coupled to a contractile-rounded, amoeboid phenotype in a panel of 16 melanoma cell lines, in mouse melanoma xenografts, and in 47 human melanoma patients. Its expression is also enriched in the invasive fronts of lesions. Functionally, we show how the TGF-β-SMAD2-CITED1 axis promotes different steps associated with progression: melanoma detachment from keratinocytes, 2D and 3D migration, attachment to endothelial cells, and in vivo lung metastatic initial colonization and outgrowth. We propose a novel mechanism by which TGF-β-induced transcription sustains actomyosin force in melanoma cells and thereby promotes melanoma progression independently of EMT.
authors.affiliation: Tumour Plasticity Laboratory, Randall Division of Cell and Molecular Biophysics, New Hunt's House, Guy's Campus, King's College London, London SE11UL, UK.
authors.forename: Gaia
authors.initials: G
authors.lastname: Cantelli
authors.affiliation: Tumour Plasticity Laboratory, Randall Division of Cell and Molecular Biophysics, New Hunt's House, Guy's Campus, King's College London, London SE11UL, UK.
authors.forename: Jose L
authors.initials: JL
authors.lastname: Orgaz
authors.affiliation: Tumour Plasticity Laboratory, Randall Division of Cell and Molecular Biophysics, New Hunt's House, Guy's Campus, King's College London, London SE11UL, UK.
authors.forename: Irene
authors.initials: I
authors.lastname: Rodriguez-Hernandez
authors.affiliation: St. John's Institute of Dermatology, Division of Genetics and Molecular Medicine, Faculty of Life Sciences and Medicine, King's College London and National Institute for Health Research (NIHR) Biomedical Research Centre at Guy's and St Thomas' Hospitals, King's College London, Guy's Campus, London SE1 9RT, UK; Department of Oncology, Haematology and Stem Cell Transplantation, University Hospital of Hamburg Eppendorf, Hamburg 20246, Germany.
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Karagiannis
authors.affiliation: Department of Pathology and Molecular Genetics, Hospital Universitari Arnau de Vilanova, University of Lleida, IRBLleida, Lleida 25198, Spain.
authors.forename: Oscar
authors.initials: O
authors.lastname: Maiques
authors.affiliation: Department of Pathology and Molecular Genetics, Hospital Universitari Arnau de Vilanova, University of Lleida, IRBLleida, Lleida 25198, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Matias-Guiu
authors.affiliation: St. John's Institute of Dermatology, Division of Genetics and Molecular Medicine, Faculty of Life Sciences and Medicine, King's College London and National Institute for Health Research (NIHR) Biomedical Research Centre at Guy's and St Thomas' Hospitals, King's College London, Guy's Campus, London SE1 9RT, UK.
authors.forename: Frank O
authors.initials: FO
authors.lastname: Nestle
authors.affiliation: Department of Dermatology, Hospital Universitari Arnau de Vilanova, University of Lleida, IRBLleida, Lleida 25198, Spain.
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Marti
authors.affiliation: St. John's Institute of Dermatology, Division of Genetics and Molecular Medicine, Faculty of Life Sciences and Medicine, King's College London and National Institute for Health Research (NIHR) Biomedical Research Centre at Guy's and St Thomas' Hospitals, King's College London, Guy's Campus, London SE1 9RT, UK.
authors.forename: Sophia N
authors.initials: SN
authors.lastname: Karagiannis
authors.affiliation: Tumour Plasticity Laboratory, Randall Division of Cell and Molecular Biophysics, New Hunt's House, Guy's Campus, King's College London, London SE11UL, UK. Electronic address: victoria.sanz_moreno@kcl.ac.uk.
authors.forename: Victoria
authors.initials: V
authors.lastname: Sanz-Moreno
mesh_terms: D000205:Actomyosin / Q000378:metabolism; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics / Q000502:physiology*; D048430:Cell Shape / Q000502:physiology; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism; D008544:Melanocytes / Q000378:metabolism / Q000473:pathology; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D009687:Nuclear Proteins / Q000378:metabolism; D051899:Smad2 Protein / Q000378:metabolism; D015534:Trans-Activators; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation; D016212:Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism* / Q000494:pharmacology; D015854:Up-Regulation
chemical_list: D051017:Apoptosis Regulatory Proteins; C512688:CITED1 protein, human; D009687:Nuclear Proteins; D051899:Smad2 Protein; D015534:Trans-Activators; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D000205:Actomyosin