Nrf2-mediated fibroblast reprogramming drives cellular senescence by targeting the matrisome

Hiebert, Paul; Wietecha, Mateusz S.; Cangkrama, Michael; Haertel, Eric; Mavrogonatou, Eleni; Stumpe, Michael; Steenbock, Heiko; Grossi, Serena; Beer, Hans-Dietmar; Angel, Peter; Brinckmann, Jürgen; Kletsas, Dimitris; Dengjel, Jörn; Werner, Sabine

doi:10.1016/j.devcel.2018.06.012

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Nrf2-mediated fibroblast reprogramming drives cellular senescence by targeting the matrisome

Hiebert, Paul Institute of Molecular Health Sciences, Department of Biology, Swiss Federal Institute of Technology (ETH) Zurich, Switzerland
Wietecha, Mateusz S. Institute of Molecular Health Sciences, Department of Biology, Swiss Federal Institute of Technology (ETH) Zurich, Switzerland
Cangkrama, Michael Institute of Molecular Health Sciences, Department of Biology, Swiss Federal Institute of Technology (ETH) Zurich, Switzerland
Haertel, Eric Institute of Molecular Health Sciences, Department of Biology, Swiss Federal Institute of Technology (ETH) Zurich, Switzerland
Mavrogonatou, Eleni Laboratory of Cell Proliferation and Ageing, Institute of Biosciences and Applications, National Centre for Scientific Research ?Demokritos?, Athens, Greece
Stumpe, Michael Department of Biology, University of Fribourg, Switzerland
Steenbock, Heiko Institute of Virology and Cell Biology, University of Lübeck, Germany
Grossi, Serena Faculty of Medicine, University of Zürich, Switzerland
Beer, Hans-Dietmar Faculty of Medicine, University of Zürich, Switzerland
Angel, Peter Division of Signal Transduction and Growth Control, German Cancer Research Center (DKFZ), Heidelberg, Germany
Brinckmann, Jürgen Institute of Virology and Cell Biology, University of Lübeck, Germany - Department of Dermatology, University of Lübeck, Germany
Kletsas, Dimitris Laboratory of Cell Proliferation and Ageing, Institute of Biosciences and Applications, National Centre for Scientific Research ?Demokritos?, Athens, Greece
Dengjel, Jörn Department of Biology, University of Fribourg, Switzerland
Werner, Sabine Institute of Molecular Health Sciences, Department of Biology, Swiss Federal Institute of Technology (ETH) Zurich, Switzerland

16.07.2018

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Developmental Cell. - 2018, vol. 46, no. 2, p. 145-161.e10

English Nrf2 is a key regulator of the antioxidant defense system, and pharmacological Nrf2 activation is a promising strategy for cancer prevention and promotion of tissue repair. Here we show, however, that activation of Nrf2 in fibroblasts induces cellular senescence. Using a combination of transcriptomics, matrix proteomics, chromatin immunoprecipitation and bioinformatics we demonstrate that fibroblasts with activated Nrf2 deposit a senescence-promoting matrix, with plasminogen activator inhibitor-1 being a key inducer of the senescence program. In vivo, activation of Nrf2 in fibroblasts promoted re-epithelialization of skin wounds, but also skin tumorigenesis. The pro-tumorigenic activity is of general relevance, since Nrf2 activation in skin fibroblasts induced the expression of genes characteristic for cancer-associated fibroblasts from different mouse and human tumors. Therefore, activated Nrf2 qualifies as a marker of the cancer-associated fibroblast phenotype. These data highlight the bright and the dark sides of Nrf2 and the need for time-controlled activation of this transcription factor.

Faculty

Faculté des sciences et de médecine

Department

Département de Biologie

Language