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Tumor Biology and Immunology

Cellular Senescence Promotes Skin Carcinogenesis through p38MAPK and p44/42MAPK Signaling

Fatouma Alimirah, Tanya Pulido, Alexis Valdovinos, Sena Alptekin, Emily Chang, Elijah Jones, Diego A. Diaz, Jose Flores, Michael C. Velarde, Marco Demaria, Albert R. Davalos, Christopher D. Wiley, Chandani Limbad, Pierre-Yves Desprez and Judith Campisi
Fatouma Alimirah
1Buck Institute for Research on Aging, Novato, California.
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Tanya Pulido
1Buck Institute for Research on Aging, Novato, California.
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Alexis Valdovinos
1Buck Institute for Research on Aging, Novato, California.
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Sena Alptekin
1Buck Institute for Research on Aging, Novato, California.
2Dokuz Eylul University School of Medicine, Izmir, Turkey.
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  • ORCID record for Sena Alptekin
Emily Chang
1Buck Institute for Research on Aging, Novato, California.
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Elijah Jones
1Buck Institute for Research on Aging, Novato, California.
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Diego A. Diaz
1Buck Institute for Research on Aging, Novato, California.
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Jose Flores
1Buck Institute for Research on Aging, Novato, California.
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Michael C. Velarde
1Buck Institute for Research on Aging, Novato, California.
3Institute of Biology, University of the Philippines Diliman, College of Science, Quezon City, Philippines.
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  • ORCID record for Michael C. Velarde
Marco Demaria
1Buck Institute for Research on Aging, Novato, California.
4European Research Institute for the Biology of Ageing, University Medical Center Groningen, Groningen, the Netherlands.
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Albert R. Davalos
1Buck Institute for Research on Aging, Novato, California.
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Christopher D. Wiley
1Buck Institute for Research on Aging, Novato, California.
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Chandani Limbad
1Buck Institute for Research on Aging, Novato, California.
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Pierre-Yves Desprez
1Buck Institute for Research on Aging, Novato, California.
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Judith Campisi
1Buck Institute for Research on Aging, Novato, California.
5Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, California.
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  • For correspondence: jcampisi@buckinstitute.org
DOI: 10.1158/0008-5472.CAN-20-0108 Published September 2020
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Graphical Abstract

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Abstract

Cellular senescence entails an irreversible growth arrest that evolved in part to prevent cancer. Paradoxically, senescent cells secrete proinflammatory and growth-stimulatory molecules, termed the senescence-associated secretory phenotype (SASP), which is correlated with cancer cell proliferation in culture and xenograft models. However, at what tumor stage and how senescence and the SASP act on endogenous tumor growth in vivo is unknown. To understand the role of senescence in cancer etiology, we subjected p16-3MR transgenic mice, which permit the identification and selective elimination of senescent cells in vivo, to the well-established two-step protocol of squamous cell skin carcinoma, in which tumorigenesis is initiated by a carcinogen 7,12-dimethylbenz[α]anthracene, and then promoted by 12-O-tetradecanoyl-phorbol-13-acetate (TPA). We show that TPA promotes skin carcinogenesis by inducing senescence and a SASP. Systemic induction of senescence in nontumor-bearing p16-3MR mice using a chemotherapy followed by the two-step carcinogenesis protocol potentiated the conversion of benign papillomas to carcinomas by elevating p38MAPK and MAPK/ERK signaling. Ablation of senescent cells reduced p38MAPK and MAPK/ERK signaling, thereby preventing the progression of benign papillomas to carcinomas. Thus, we show for the first time that senescent cells are tumor promoters, not tumor initiators, and that they stimulate skin carcinogenesis by elevating p38MAPK and MAPK/ERK signaling. These findings pave the way for developing novel therapeutics against senescence-fueled cancers.

Significance: These findings identify chemotherapy-induced senescence as a culprit behind tumor promotion, suggesting that elimination of senescent cells after chemotherapy may reduce occurrence of second cancers decades later.

Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/80/17/3606/F1.large.jpg.

Footnotes

  • Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).

  • Cancer Res 2020;80:3606–19

  • Received January 13, 2020.
  • Revision received May 9, 2020.
  • Accepted June 29, 2020.
  • Published first July 8, 2020.
  • ©2020 American Association for Cancer Research.
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Cancer Research: 80 (17)
September 2020
Volume 80, Issue 17
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Cellular Senescence Promotes Skin Carcinogenesis through p38MAPK and p44/42MAPK Signaling
Fatouma Alimirah, Tanya Pulido, Alexis Valdovinos, Sena Alptekin, Emily Chang, Elijah Jones, Diego A. Diaz, Jose Flores, Michael C. Velarde, Marco Demaria, Albert R. Davalos, Christopher D. Wiley, Chandani Limbad, Pierre-Yves Desprez and Judith Campisi
Cancer Res September 1 2020 (80) (17) 3606-3619; DOI: 10.1158/0008-5472.CAN-20-0108

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Cellular Senescence Promotes Skin Carcinogenesis through p38MAPK and p44/42MAPK Signaling
Fatouma Alimirah, Tanya Pulido, Alexis Valdovinos, Sena Alptekin, Emily Chang, Elijah Jones, Diego A. Diaz, Jose Flores, Michael C. Velarde, Marco Demaria, Albert R. Davalos, Christopher D. Wiley, Chandani Limbad, Pierre-Yves Desprez and Judith Campisi
Cancer Res September 1 2020 (80) (17) 3606-3619; DOI: 10.1158/0008-5472.CAN-20-0108
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