title: Epigenetic switch drives the conversion of fibroblasts into proinvasive cancer-associated fibroblasts.
abstract: Carcinoma-associated fibroblasts (CAF) mediate the onset of a proinvasive tumour microenvironment. The proinflammatory cytokine LIF reprograms fibroblasts into a proinvasive phenotype, which promotes extracellular matrix remodelling and collective invasion of cancer cells. Here we unveil that exposure to LIF initiates an epigenetic switch leading to the constitutive activation of JAK1/STAT3 signalling, which results in sustained proinvasive activity of CAF. Mechanistically, p300-histone acetyltransferase acetylates STAT3, which, in turn, upregulates and activates the DNMT3b DNA methyltransferase. DNMT3b methylates CpG sites of the SHP-1 phosphatase promoter, which abrogates SHP-1 expression, and results in constitutive phosphorylation of JAK1. Sustained JAK1/STAT3 signalling is maintained by DNA methyltransferase DNMT1. Consistently, in human lung and head and neck carcinomas, STAT3 acetylation and phosphorylation are inversely correlated with SHP-1 expression. Combined inhibition of DNMT activities and JAK signalling, in vitro and in vivo, results in long-term reversion of CAF-associated proinvasive activity and restoration of the wild-type fibroblast phenotype.
authors.affiliation: INSERM U1081, CNRS UMR7284, Institute for Research on Cancer and Aging, Nice (IRCAN), University of Nice Sophia Antipolis, Medical School, 28 Avenue Valombrose, Nice F-06107, France.
authors.forename: Jean
authors.initials: J
authors.lastname: Albrengues
authors.affiliation: INSERM U1081, CNRS UMR7284, Institute for Research on Cancer and Aging, Nice (IRCAN), University of Nice Sophia Antipolis, Medical School, 28 Avenue Valombrose, Nice F-06107, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Bertero
authors.affiliation: INSERM U1081, CNRS UMR7284, Institute for Research on Cancer and Aging, Nice (IRCAN), University of Nice Sophia Antipolis, Medical School, 28 Avenue Valombrose, Nice F-06107, France.
authors.forename: Eloise
authors.initials: E
authors.lastname: Grasset
authors.affiliation: INSERM U1081, CNRS UMR7284, Institute for Research on Cancer and Aging, Nice (IRCAN), University of Nice Sophia Antipolis, Medical School, 28 Avenue Valombrose, Nice F-06107, France.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Bonan
authors.affiliation: INSERM U1081, CNRS UMR7284, Institute for Research on Cancer and Aging, Nice (IRCAN), University of Nice Sophia Antipolis, Medical School, 28 Avenue Valombrose, Nice F-06107, France.
authors.forename: Majdi
authors.initials: M
authors.lastname: Maiel
authors.affiliation: INSERM U1081, CNRS UMR7284, Institute for Research on Cancer and Aging, Nice (IRCAN), University of Nice Sophia Antipolis, Medical School, 28 Avenue Valombrose, Nice F-06107, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Bourget
authors.affiliation: INSERM U1081, CNRS UMR7284, Institute for Research on Cancer and Aging, Nice (IRCAN), University of Nice Sophia Antipolis, Medical School, 28 Avenue Valombrose, Nice F-06107, France.
authors.forename: Claude
authors.initials: C
authors.lastname: Philippe
authors.affiliation: Tumour Plasticity Laboratory, Randall Division of Cell and Molecular Biophysics, New Hunt's House, Guy's Campus, King's College London, London SE1UL, UK.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Herraiz Serrano
authors.affiliation: CNRS UMR 7278, IFR48, Unité de Recherche sur les Maladies Infectieuses et Tropicales Emergentes, Faculté de Médecine, Aix-Marseille Université, 13385 Marseille Cedex 05, France.
authors.forename: Samia
authors.initials: S
authors.lastname: Benamar
authors.affiliation: INSERM U1081, CNRS UMR7284, Institute for Research on Cancer and Aging, Nice (IRCAN), University of Nice Sophia Antipolis, Medical School, 28 Avenue Valombrose, Nice F-06107, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Croce
authors.affiliation: Tumour Plasticity Laboratory, Randall Division of Cell and Molecular Biophysics, New Hunt's House, Guy's Campus, King's College London, London SE1UL, UK.
authors.forename: Victoria
authors.initials: V
authors.lastname: Sanz-Moreno
authors.affiliation: INSERM U1081, CNRS UMR7284, Institute for Research on Cancer and Aging, Nice (IRCAN), University of Nice Sophia Antipolis, Medical School, 28 Avenue Valombrose, Nice F-06107, France.
authors.forename: Guerrino
authors.initials: G
authors.lastname: Meneguzzi
authors.affiliation: INSERM U1081, CNRS UMR7284, Institute for Research on Cancer and Aging, Nice (IRCAN), University of Nice Sophia Antipolis, Medical School, 28 Avenue Valombrose, Nice F-06107, France.
authors.forename: Chloe C
authors.initials: CC
authors.lastname: Feral
authors.affiliation: INSERM U1081, CNRS UMR7284, Institute for Research on Cancer and Aging, Nice (IRCAN), University of Nice Sophia Antipolis, Medical School, 28 Avenue Valombrose, Nice F-06107, France.
authors.forename: Gael
authors.initials: G
authors.lastname: Cristofari
authors.affiliation: INSERM U1081, CNRS UMR7284, Institute for Research on Cancer and Aging, Nice (IRCAN), University of Nice Sophia Antipolis, Medical School, 28 Avenue Valombrose, Nice F-06107, France.
authors.forename: Cedric
authors.initials: C
authors.lastname: Gaggioli
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D057890:Epigenomics; D005260:Female; D005347:Fibroblasts / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000378:metabolism*; D009374:Neoplasms, Experimental / Q000378:metabolism; D034622:RNA Interference
chemical_list: D057134:Antibodies, Neutralizing; D016207:Cytokines