Epigenetic switch drives the conversion of fibroblasts into proinvasive cancer-associated fibroblasts

Jean Albrengues, Thomas Bertero, Eloise Grasset, Stephanie Bonan, Majdi Maiel, Isabelle Bourget, Claude Philippe, Cecilia Herraiz Serrano, Samia Benamar, Olivier Croce, Victoria Sanz-Moreno, Guerrino Meneguzzi, Chloe C. Feral, Gael Cristofari and Cedric Gaggioli ()
Additional contact information
Jean Albrengues: INSERM U1081, CNRS UMR7284, Institute for Research on Cancer and Aging, Nice (IRCAN), University of Nice Sophia Antipolis, Medical School
Thomas Bertero: INSERM U1081, CNRS UMR7284, Institute for Research on Cancer and Aging, Nice (IRCAN), University of Nice Sophia Antipolis, Medical School
Eloise Grasset: INSERM U1081, CNRS UMR7284, Institute for Research on Cancer and Aging, Nice (IRCAN), University of Nice Sophia Antipolis, Medical School
Stephanie Bonan: INSERM U1081, CNRS UMR7284, Institute for Research on Cancer and Aging, Nice (IRCAN), University of Nice Sophia Antipolis, Medical School
Majdi Maiel: INSERM U1081, CNRS UMR7284, Institute for Research on Cancer and Aging, Nice (IRCAN), University of Nice Sophia Antipolis, Medical School
Isabelle Bourget: INSERM U1081, CNRS UMR7284, Institute for Research on Cancer and Aging, Nice (IRCAN), University of Nice Sophia Antipolis, Medical School
Claude Philippe: INSERM U1081, CNRS UMR7284, Institute for Research on Cancer and Aging, Nice (IRCAN), University of Nice Sophia Antipolis, Medical School
Cecilia Herraiz Serrano: Tumour Plasticity Laboratory, New Hunt’s House, Guy’s Campus, King’s College London
Samia Benamar: CNRS UMR 7278, IFR48, Unité de Recherche sur les Maladies Infectieuses et Tropicales Emergentes, Faculté de Médecine, Aix-Marseille Université
Olivier Croce: INSERM U1081, CNRS UMR7284, Institute for Research on Cancer and Aging, Nice (IRCAN), University of Nice Sophia Antipolis, Medical School
Victoria Sanz-Moreno: Tumour Plasticity Laboratory, New Hunt’s House, Guy’s Campus, King’s College London
Guerrino Meneguzzi: INSERM U1081, CNRS UMR7284, Institute for Research on Cancer and Aging, Nice (IRCAN), University of Nice Sophia Antipolis, Medical School
Chloe C. Feral: INSERM U1081, CNRS UMR7284, Institute for Research on Cancer and Aging, Nice (IRCAN), University of Nice Sophia Antipolis, Medical School
Gael Cristofari: INSERM U1081, CNRS UMR7284, Institute for Research on Cancer and Aging, Nice (IRCAN), University of Nice Sophia Antipolis, Medical School
Cedric Gaggioli: INSERM U1081, CNRS UMR7284, Institute for Research on Cancer and Aging, Nice (IRCAN), University of Nice Sophia Antipolis, Medical School

Nature Communications, 2015, vol. 6, issue 1, 1-15

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms10204

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