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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 (2018). Nrf2-mediated fibroblast reprogramming drives cellular senescence by targeting the matrisome. Developmental Cell, 46(2):145-161.

Abstract

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.

Abstract

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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Dermatology Clinic
Dewey Decimal Classification:610 Medicine & health
Uncontrolled Keywords:Developmental Biology
Language:English
Date:2018
Deposited On:24 Aug 2018 17:32
Last Modified:24 Aug 2018 17:32
Publisher:Cell Press (Elsevier)
ISSN:1534-5807
OA Status:Closed
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1016/j.devcel.2018.06.012
PubMed ID:30016619
Project Information:
  • : FunderSNSF
  • : Grant ID31003A_169204
  • : Project TitleRole of cytokines and environmental cues in wound repair and inflammatory skin disease
  • : FunderSNSF
  • : Grant ID310030_132884
  • : Project TitleFibroblast growth factor signaling in skin barrier function, wound repair and inflammatory skin disease

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