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; Cedric Gaggioli

doi:10.1038/ncomms10204

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, Cedric Gaggioli^*

^*Corresponding author for this work

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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.

Original language	English
Article number	10204
Journal	Nature Communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms10204
Publication status	Published - 15 Dec 2015

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Albrengues, J., Bertero, T., Grasset, E., Bonan, S., Maiel, M., Bourget, I., Philippe, C., Herraiz Serrano, C., Benamar, S., Croce, O., Sanz-Moreno, V., Meneguzzi, G., Feral, C. C., Cristofari, G., & Gaggioli, C. (2015). Epigenetic switch drives the conversion of fibroblasts into proinvasive cancer-associated fibroblasts. Nature Communications, 6, Article 10204. https://doi.org/10.1038/ncomms10204

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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.",

author = "Jean Albrengues and Thomas Bertero and Eloise Grasset and Stephanie Bonan and Majdi Maiel and Isabelle Bourget and Claude Philippe and {Herraiz Serrano}, Cecilia and Samia Benamar and Olivier Croce and Victoria Sanz-Moreno and Guerrino Meneguzzi and Feral, {Chloe C.} and Gael Cristofari and Cedric Gaggioli",

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Albrengues, J, Bertero, T, Grasset, E, Bonan, S, Maiel, M, Bourget, I, Philippe, C, Herraiz Serrano, C, Benamar, S, Croce, O, Sanz-Moreno, V, Meneguzzi, G, Feral, CC, Cristofari, G & Gaggioli, C 2015, 'Epigenetic switch drives the conversion of fibroblasts into proinvasive cancer-associated fibroblasts', Nature Communications, vol. 6, 10204. https://doi.org/10.1038/ncomms10204

TY - JOUR

T1 - Epigenetic switch drives the conversion of fibroblasts into proinvasive cancer-associated fibroblasts

AU - Albrengues, Jean

AU - Bertero, Thomas

AU - Grasset, Eloise

AU - Bonan, Stephanie

AU - Maiel, Majdi

AU - Bourget, Isabelle

AU - Philippe, Claude

AU - Herraiz Serrano, Cecilia

AU - Benamar, Samia

AU - Croce, Olivier

AU - Sanz-Moreno, Victoria

AU - Meneguzzi, Guerrino

AU - Feral, Chloe C.

AU - Cristofari, Gael

AU - Gaggioli, Cedric

PY - 2015/12/15

Y1 - 2015/12/15

N2 - 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.

AB - 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.

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U2 - 10.1038/ncomms10204

DO - 10.1038/ncomms10204

M3 - Article

AN - SCOPUS:84950129821

SN - 2041-1723

VL - 6

JO - Nature Communications

JF - Nature Communications

M1 - 10204

ER -

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

Abstract

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