Nrf2-Mediated Fibroblast Reprogramming Drives Cellular Senescence by Targeting the Matrisome

• Published in: Developmental cell Vol. 46; no. 2; pp. 145 - 161.e10
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 16.07.2018
• Subjects: Animals; Antioxidants - metabolism; cancer; cancer-associated fibroblast; Carcinogenesis - metabolism; Cell Proliferation; Cellular Reprogramming - physiology; Cellular Senescence - physiology; extracellular matrix; Extracellular Matrix - physiology; fibroblast; Fibroblasts - physiology; Gene Expression Regulation - physiology; Mice; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - metabolism; NF-E2-Related Factor 2 - physiology; Nrf2; Oxidative Stress - physiology; SASP; senescence; Skin - metabolism; wound healing; Wound Healing - physiology; cancer-associated fibroblast; senescence; wound healing; fibroblast; Nrf2; cancer; SASP; extracellular matrix
• ISSN: 1534-5807; 1878-1551; 1878-1551
• DOI: 10.1016/j.devcel.2018.06.012

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. •Prolonged activation of Nrf2 promotes fibroblast senescence•Nrf2 controls expression and secretion of extracellular matrix components•Nrf2 activation induces a cancer-associated fibroblast phenotype•Senescent fibroblasts with activated Nrf2 promote wound closure but also tumorigenesis Activation of the cytoprotective transcription factor Nrf2 is considered as a strategy for disease prevention. Hiebert et al. show that activating Nrf2 in fibroblasts promotes cellular senescence through production of a senescence-promoting matrisome, leading to accelerated wound closure but also increased tumor growth.