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

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

doi:10.1016/j.devcel.2018.06.012

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

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

^*Corresponding author for this work

Clinic of Dermatology, Allergology and Venerology

154 Citations (Scopus)

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.

Original language	English
Journal	Developmental Cell
Volume	46
Issue number	2
Pages (from-to)	145-161.e10
ISSN	1534-5807
DOIs	https://doi.org/10.1016/j.devcel.2018.06.012
Publication status	Published - 16.07.2018

Funding

We thank Dr. Svitlana Kurinna, ETH Zurich, for help with the ChIP experiments, Prof. Gian-Paolo Dotto and Pino Bordignon, University of Lausanne, for help with ear tumorigenesis experiments, Joohee Lee and Christiane Born-Berclaz, ETH Zurich, for invaluable experimental help, and Drs. Hubert Rehrauer, Jelena Kühn Georgijevic, and Francesc Castro-Giner (Functional Genomics Center Zurich) for RNA sequencing. We further thank Dr. Shyam Biswal, Johns Hopkins University, Baltimore, MD, for the conditional Nrf2 knockout mice and Drs. Jeffrey and Delinda Johnson, University of Wisconsin-Madison, WI, for ARE reporter mice. This work was supported by grants from the Swiss National Science Foundation ( 310030_132884 and 31003A_169204 to S.W.), the Wilhelm Sander-Stiftung (to S.W.), the Swiss Cancer League ( KFS-3474-08-2014 to S.W.), and a Banting postdoctoral fellowship (to P.H.).

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Research Areas and Centers

Academic Focus: Center for Infection and Inflammation Research (ZIEL)

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10.1016/j.devcel.2018.06.012

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Hiebert, P., Wietecha, M. S., Cangkrama, M., Haertel, E., Mavrogonatou, E., Stumpe, M., Steenbock, H., Grossi, S., Beer, H. D., Angel, P., Brinckmann, J., Kletsas, D., Dengjel, J., & Werner, S. (2018). Nrf2-Mediated Fibroblast Reprogramming Drives Cellular Senescence by Targeting the Matrisome. Developmental Cell, 46(2), 145-161.e10. https://doi.org/10.1016/j.devcel.2018.06.012

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title = "Nrf2-Mediated Fibroblast Reprogramming Drives Cellular Senescence by Targeting the Matrisome",

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.",

author = "Paul Hiebert and Wietecha, \{Mateusz S.\} and Michael Cangkrama and Eric Haertel and Eleni Mavrogonatou and Michael Stumpe and Heiko Steenbock and Serena Grossi and Beer, \{Hans Dietmar\} and Peter Angel and J{\"u}rgen Brinckmann and Dimitris Kletsas and J{\"o}rn Dengjel and Sabine Werner",

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Hiebert, P, Wietecha, MS, Cangkrama, M, Haertel, E, Mavrogonatou, E, Stumpe, M, Steenbock, H, Grossi, S, Beer, HD, Angel, P, Brinckmann, J, Kletsas, D, Dengjel, J & Werner, S 2018, 'Nrf2-Mediated Fibroblast Reprogramming Drives Cellular Senescence by Targeting the Matrisome', Developmental Cell, vol. 46, no. 2, pp. 145-161.e10. https://doi.org/10.1016/j.devcel.2018.06.012

TY - JOUR

T1 - Nrf2-Mediated Fibroblast Reprogramming Drives Cellular Senescence by Targeting the Matrisome

AU - Hiebert, Paul

AU - Wietecha, Mateusz S.

AU - Cangkrama, Michael

AU - Haertel, Eric

AU - Mavrogonatou, Eleni

AU - Stumpe, Michael

AU - Steenbock, Heiko

AU - Grossi, Serena

AU - Beer, Hans Dietmar

AU - Angel, Peter

AU - Brinckmann, Jürgen

AU - Kletsas, Dimitris

AU - Dengjel, Jörn

AU - Werner, Sabine

PY - 2018/7/16

Y1 - 2018/7/16

N2 - 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.

AB - 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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M3 - Journal articles

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AN - SCOPUS:85049346475

SN - 1534-5807

VL - 46

SP - 145-161.e10

JO - Developmental Cell

JF - Developmental Cell

IS - 2

ER -

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

Abstract

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