title: The NADPH oxidase NOX4 represses epithelial to amoeboid transition and efficient tumour dissemination.
abstract: Epithelial to mesenchymal transition is a common event during tumour dissemination. However, direct epithelial to amoeboid transition has not been characterized to date. Here we provide evidence that cells from hepatocellular carcinoma (HCC), a highly metastatic cancer, undergo epithelial to amoeboid transition in physiological environments, such as organoids or three-dimensional complex matrices. Furthermore, the NADPH oxidase NOX4 inhibits this transition and therefore suppresses efficient amoeboid bleb-based invasion. Moreover, NOX4 expression is associated with E-cadherin levels and inversely correlated with invasive features. NOX4 is necessary to maintain parenchymal structures, increase cell-cell and cell-to-matrix adhesion, and impair actomyosin contractility and amoeboid invasion. Importantly, NOX4 gene deletions are frequent in HCC patients, correlating with higher tumour grade. Contrary to that observed in mesenchymal cell types, here NOX4 suppresses Rho and Cdc42 GTPase expression and downstream actomyosin contractility. In HCC patients, NOX4 expression inversely correlates with RhoC and Cdc42 levels. Moreover, low expression of NOX4 combined with high expression of either RhoC or Cdc42 is associated with worse prognosis. Therefore, loss of NOX4 increases actomyosin levels and favours an epithelial to amoeboid transition contributing to tumour aggressiveness.
authors.affiliation: Molecular Oncology, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.|Tumour Plasticity Laboratory, Randall Division of Cell and Molecular Biophysics, New Hunt's House, Guy's Campus, King's College London, London, UK.
authors.forename: E
authors.initials: E
authors.lastname: Crosas-Molist
authors.affiliation: Molecular Oncology, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Bertran
authors.affiliation: Tumour Plasticity Laboratory, Randall Division of Cell and Molecular Biophysics, New Hunt's House, Guy's Campus, King's College London, London, UK.
authors.forename: I
authors.initials: I
authors.lastname: Rodriguez-Hernandez
authors.affiliation: Tumour Plasticity Laboratory, Randall Division of Cell and Molecular Biophysics, New Hunt's House, Guy's Campus, King's College London, London, UK.
authors.forename: C
authors.initials: C
authors.lastname: Herraiz
authors.affiliation: Tumour Plasticity Laboratory, Randall Division of Cell and Molecular Biophysics, New Hunt's House, Guy's Campus, King's College London, London, UK.
authors.forename: G
authors.initials: G
authors.lastname: Cantelli
authors.affiliation: Molecular Oncology, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: À
authors.initials: À
authors.lastname: Fabra
authors.affiliation: Tumour Plasticity Laboratory, Randall Division of Cell and Molecular Biophysics, New Hunt's House, Guy's Campus, King's College London, London, UK.
authors.forename: V
authors.identifier: 0000-0002-5096-9456
authors.initials: V
authors.lastname: Sanz-Moreno
authors.affiliation: Molecular Oncology, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.|Departament de Ciències Fisiològiques II, University of Barcelona, Barcelona, Spain.
authors.forename: I
authors.initials: I
authors.lastname: Fabregat
mesh_terms: D000205:Actomyosin / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000473:pathology*; D002448:Cell Adhesion / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D020869:Gene Expression Profiling; D016147:Genes, Tumor Suppressor / Q000502:physiology; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology*; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000502:physiology*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis
chemical_list: D000205:Actomyosin; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498910:NOX4 protein, human