IDEAS home Printed from https://ideas.repec.org/a/plo/pbio00/0060301.html
   My bibliography  Save this article

Senescence-Associated Secretory Phenotypes Reveal Cell-Nonautonomous Functions of Oncogenic RAS and the p53 Tumor Suppressor

Author

Listed:
  • Jean-Philippe Coppé
  • Christopher K Patil
  • Francis Rodier
  • Yu Sun
  • Denise P Muñoz
  • Joshua Goldstein
  • Peter S Nelson
  • Pierre-Yves Desprez
  • Judith Campisi

Abstract

Cellular senescence suppresses cancer by arresting cell proliferation, essentially permanently, in response to oncogenic stimuli, including genotoxic stress. We modified the use of antibody arrays to provide a quantitative assessment of factors secreted by senescent cells. We show that human cells induced to senesce by genotoxic stress secrete myriad factors associated with inflammation and malignancy. This senescence-associated secretory phenotype (SASP) developed slowly over several days and only after DNA damage of sufficient magnitude to induce senescence. Remarkably similar SASPs developed in normal fibroblasts, normal epithelial cells, and epithelial tumor cells after genotoxic stress in culture, and in epithelial tumor cells in vivo after treatment of prostate cancer patients with DNA-damaging chemotherapy. In cultured premalignant epithelial cells, SASPs induced an epithelial–mesenchyme transition and invasiveness, hallmarks of malignancy, by a paracrine mechanism that depended largely on the SASP factors interleukin (IL)-6 and IL-8. Strikingly, two manipulations markedly amplified, and accelerated development of, the SASPs: oncogenic RAS expression, which causes genotoxic stress and senescence in normal cells, and functional loss of the p53 tumor suppressor protein. Both loss of p53 and gain of oncogenic RAS also exacerbated the promalignant paracrine activities of the SASPs. Our findings define a central feature of genotoxic stress-induced senescence. Moreover, they suggest a cell-nonautonomous mechanism by which p53 can restrain, and oncogenic RAS can promote, the development of age-related cancer by altering the tissue microenvironment. : Cells with damaged DNA are at risk of becoming cancerous tumors. Although “cellular senescence” can suppress tumor formation from damaged cells by blocking the cell division that underlies cancer growth, it has also been implicated in promoting cancer and other age-related diseases. To understand how this might happen, we measured proteins that senescent human cells secrete into their local environment and found many factors associated with inflammation and cancer development. Different types of cells secrete a common set of proteins when they senesce. This senescence-associated secretory phenotype (SASP) occurs not only in cultured cells, but also in vivo in response to DNA-damaging chemotherapy. Normal cells that acquire a highly active mutant version of the RAS protein, which is known to contribute to tumor growth, undergo cellular senescence, and develop a very intense SASP, with higher levels of proteins secreted. Likewise, the SASP is more intense when cells lose the functions of the tumor suppressor p53. Senescent cells promote the growth and aggressiveness of nearby precancerous or cancer cells, and cells with a more intense SASP do so more efficiently. Our findings support the idea that cellular senescence can be both beneficial, in preventing damaged cells from dividing, and deleterious, by having effects on neighboring cells; this balance of effects is predicted by an evolutionary theory of aging. By controlling how damaged cells modify their surrounding tissue environment, a tumor suppressor gene can restrain, and an oncogene can promote, the development of cancer.

Suggested Citation

  • Jean-Philippe Coppé & Christopher K Patil & Francis Rodier & Yu Sun & Denise P Muñoz & Joshua Goldstein & Peter S Nelson & Pierre-Yves Desprez & Judith Campisi, 2008. "Senescence-Associated Secretory Phenotypes Reveal Cell-Nonautonomous Functions of Oncogenic RAS and the p53 Tumor Suppressor," PLOS Biology, Public Library of Science, vol. 6(12), pages 1-1, December.
  • Handle: RePEc:plo:pbio00:0060301
    DOI: 10.1371/journal.pbio.0060301
    as

    Download full text from publisher

    File URL: https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.0060301
    Download Restriction: no

    File URL: https://journals.plos.org/plosbiology/article/file?id=10.1371/journal.pbio.0060301&type=printable
    Download Restriction: no

    File URL: https://libkey.io/10.1371/journal.pbio.0060301?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Chrysiis Michaloglou & Liesbeth C. W. Vredeveld & Maria S. Soengas & Christophe Denoyelle & Thomas Kuilman & Chantal M. A. M. van der Horst & Donné M. Majoor & Jerry W. Shay & Wolter J. Mooi & Daniel , 2005. "BRAFE600-associated senescence-like cell cycle arrest of human naevi," Nature, Nature, vol. 436(7051), pages 720-724, August.
    2. Andrea Ventura & David G. Kirsch & Margaret E. McLaughlin & David A. Tuveson & Jan Grimm & Laura Lintault & Jamie Newman & Elizabeth E. Reczek & Ralph Weissleder & Tyler Jacks, 2007. "Restoration of p53 function leads to tumour regression in vivo," Nature, Nature, vol. 445(7128), pages 661-665, February.
    3. Manuel Collado & Jesús Gil & Alejo Efeyan & Carmen Guerra & Alberto J. Schuhmacher & Marta Barradas & Alberto Benguría & Angel Zaballos & Juana M. Flores & Mariano Barbacid & David Beach & Manuel Serr, 2005. "Senescence in premalignant tumours," Nature, Nature, vol. 436(7051), pages 642-642, August.
    4. Vassilis G. Gorgoulis & Leandros-Vassilios F. Vassiliou & Panagiotis Karakaidos & Panayotis Zacharatos & Athanassios Kotsinas & Triantafillos Liloglou & Monica Venere & Richard A. DiTullio & Nikolaos , 2005. "Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions," Nature, Nature, vol. 434(7035), pages 907-913, April.
    5. Stuart D. Tyner & Sundaresan Venkatachalam & Jene Choi & Stephen Jones & Nader Ghebranious & Herbert Igelmann & Xiongbin Lu & Gabrielle Soron & Benjamin Cooper & Cory Brayton & Sang Hee Park & Timothy, 2002. "p53 mutant mice that display early ageing-associated phenotypes," Nature, Nature, vol. 415(6867), pages 45-53, January.
    6. Thomas B. L. Kirkwood & Steven N. Austad, 2000. "Why do we age?," Nature, Nature, vol. 408(6809), pages 233-238, November.
    7. Wen Xue & Lars Zender & Cornelius Miething & Ross A. Dickins & Eva Hernando & Valery Krizhanovsky & Carlos Cordon-Cardo & Scott W. Lowe, 2007. "Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas," Nature, Nature, vol. 445(7128), pages 656-660, February.
    8. Jirina Bartkova & Zuzana Hořejší & Karen Koed & Alwin Krämer & Frederic Tort & Karsten Zieger & Per Guldberg & Maxwell Sehested & Jahn M. Nesland & Claudia Lukas & Torben Ørntoft & Jiri Lukas & Jiri B, 2005. "DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis," Nature, Nature, vol. 434(7035), pages 864-870, April.
    9. Melanie Braig & Soyoung Lee & Christoph Loddenkemper & Cornelia Rudolph & Antoine H.F.M. Peters & Brigitte Schlegelberger & Harald Stein & Bernd Dörken & Thomas Jenuwein & Clemens A. Schmitt, 2005. "Oncogene-induced senescence as an initial barrier in lymphoma development," Nature, Nature, vol. 436(7051), pages 660-665, August.
    10. Raffaella Di Micco & Marzia Fumagalli & Angelo Cicalese & Sara Piccinin & Patrizia Gasparini & Chiara Luise & Catherine Schurra & Massimiliano Garre’ & Paolo Giovanni Nuciforo & Aaron Bensimon & Rober, 2006. "Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication," Nature, Nature, vol. 444(7119), pages 638-642, November.
    Full references (including those not matched with items on IDEAS)

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. Alka Gupta & Parminder Singh, 2019. "Newly Discovered Molecules as Potential Candidates for Treating Osteoporosis," Global Journal of Pharmacy & Pharmaceutical Sciences, Juniper Publishers Inc., vol. 7(3), pages 91-93, July.
    2. Jina Yun & Simon Hansen & Otto Morris & David T. Madden & Clare Peters Libeu & Arjun J. Kumar & Cameron Wehrfritz & Aaron H. Nile & Yingnan Zhang & Lijuan Zhou & Yuxin Liang & Zora Modrusan & Michelle, 2023. "Senescent cells perturb intestinal stem cell differentiation through Ptk7 induced noncanonical Wnt and YAP signaling," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    3. Huiru Bai & Xiaoqin Liu & Meizhen Lin & Yuan Meng & Ruolan Tang & Yajing Guo & Nan Li & Michael F. Clarke & Shang Cai, 2024. "Progressive senescence programs induce intrinsic vulnerability to aging-related female breast cancer," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    4. Ines Sturmlechner & Chance C. Sine & Karthik B. Jeganathan & Cheng Zhang & Raul O. Fierro Velasco & Darren J. Baker & Hu Li & Jan M. Deursen, 2022. "Senescent cells limit p53 activity via multiple mechanisms to remain viable," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    5. Cox, Lynne S., 2022. "Therapeutic approaches to treat and prevent age-related diseases through understanding the underlying biological drivers of ageing," The Journal of the Economics of Ageing, Elsevier, vol. 23(C).
    6. Stacy A. Hussong & Andy Q. Banh & Candice E. Skike & Angela O. Dorigatti & Stephen F. Hernandez & Matthew J. Hart & Beatriz Ferran & Haneen Makhlouf & Maria Gaczynska & Pawel A. Osmulski & Salome A. M, 2023. "Soluble pathogenic tau enters brain vascular endothelial cells and drives cellular senescence and brain microvascular dysfunction in a mouse model of tauopathy," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Yukinari Haraoka & Yuki Akieda & Yuri Nagai & Chihiro Mogi & Tohru Ishitani, 2022. "Zebrafish imaging reveals TP53 mutation switching oncogene-induced senescence from suppressor to driver in primary tumorigenesis," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    2. Wei Wu & Szymon A. Barwacz & Rahul Bhowmick & Katrine Lundgaard & Marisa M. Gonçalves Dinis & Malgorzata Clausen & Masato T. Kanemaki & Ying Liu, 2023. "Mitotic DNA synthesis in response to replication stress requires the sequential action of DNA polymerases zeta and delta in human cells," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    3. Samuel A Danziger & Roberta Baronio & Lydia Ho & Linda Hall & Kirsty Salmon & G Wesley Hatfield & Peter Kaiser & Richard H Lathrop, 2009. "Predicting Positive p53 Cancer Rescue Regions Using Most Informative Positive (MIP) Active Learning," PLOS Computational Biology, Public Library of Science, vol. 5(9), pages 1-12, September.
    4. Hervé Técher & Diyavarshini Gopaul & Jonathan Heuzé & Nail Bouzalmad & Baptiste Leray & Audrey Vernet & Clément Mettling & Jérôme Moreaux & Philippe Pasero & Yea-Lih Lin, 2024. "MRE11 and TREX1 control senescence by coordinating replication stress and interferon signaling," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    5. Marc A. Vittoria & Nathan Kingston & Kristyna Kotynkova & Eric Xia & Rui Hong & Lee Huang & Shayna McDonald & Andrew Tilston-Lunel & Revati Darp & Joshua D. Campbell & Deborah Lang & Xiaowei Xu & Crai, 2022. "Inactivation of the Hippo tumor suppressor pathway promotes melanoma," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    6. Simão, Éder M. & Cabral, Heleno B. & Castro, Mauro A.A. & Sinigaglia, Marialva & Mombach, José C.M. & Librelotto, Giovani R., 2010. "Modeling the Human Genome Maintenance network," Physica A: Statistical Mechanics and its Applications, Elsevier, vol. 389(19), pages 4188-4194.
    7. Tomoko Yamamori Morita & Jie Yu & Yukie Kashima & Ryo Kamata & Gaku Yamamoto & Tatsunori Minamide & Chiaki Mashima & Miyuki Yoshiya & Yuta Sakae & Toyohiro Yamauchi & Yumi Hakozaki & Shun-ichiro Kagey, 2023. "CDC7 inhibition induces replication stress-mediated aneuploid cells with an inflammatory phenotype sensitizing tumors to immune checkpoint blockade," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    8. Jonuelle Acosta & Qinglan Li & Nelson F. Freeburg & Nivitha Murali & Alexandra Indeglia & Grant P. Grothusen & Michelle Cicchini & Hung Mai & Amy C. Gladstein & Keren M. Adler & Katherine R. Doerig & , 2023. "p53 restoration in small cell lung cancer identifies a latent cyclophilin-dependent necrosis mechanism," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    9. Devashish Dwivedi & Daniela Harry & Patrick Meraldi, 2023. "Mild replication stress causes premature centriole disengagement via a sub-critical Plk1 activity under the control of ATR-Chk1," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    10. Kristoffer Sølvsten Burgdorf & Niels Grarup & Johanne Marie Justesen & Marie Neergaard Harder & Daniel Rinse Witte & Torben Jørgensen & Annelli Sandbæk & Torsten Lauritzen & Sten Madsbad & Torben Hans, 2011. "Studies of the Association of Arg72Pro of Tumor Suppressor Protein p53 with Type 2 Diabetes in a Combined Analysis of 55,521 Europeans," PLOS ONE, Public Library of Science, vol. 6(1), pages 1-6, January.
    11. Taichi Igarashi & Marianne Mazevet & Takaaki Yasuhara & Kimiyoshi Yano & Akifumi Mochizuki & Makoto Nishino & Tatsuya Yoshida & Yukihiro Yoshida & Nobuhiko Takamatsu & Akihide Yoshimi & Kouya Shiraish, 2023. "An ATR-PrimPol pathway confers tolerance to oncogenic KRAS-induced and heterochromatin-associated replication stress," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    12. Mariana Shumliakivska & Guillermo Luxán & Inga Hemmerling & Marina Scheller & Xue Li & Carsten Müller-Tidow & Bianca Schuhmacher & Zhengwu Sun & Andreas Dendorfer & Alisa Debes & Simone-Franziska Glas, 2024. "DNMT3A clonal hematopoiesis-driver mutations induce cardiac fibrosis by paracrine activation of fibroblasts," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    13. Wassim Abou-Jaoudé & Madalena Chaves & Jean-Luc Gouzé, 2011. "A Theoretical Exploration of Birhythmicity in the p53-Mdm2 Network," PLOS ONE, Public Library of Science, vol. 6(2), pages 1-12, February.
    14. Heijdra, Ben J. & Romp, Ward E., 2009. "Human capital formation and macroeconomic performance in an ageing small open economy," Journal of Economic Dynamics and Control, Elsevier, vol. 33(3), pages 725-744, March.
    15. Cesarini, David & Lindqvist, Erik & Wallace, Björn, 2007. "Maternal Longevity and the Sex of Offspring: Evidence from Pre-Industrial Sweden," SSE/EFI Working Paper Series in Economics and Finance 651, Stockholm School of Economics.
    16. Jaskaren Kohli & Chen Ge & Eleni Fitsiou & Miriam Doepner & Simone M. Brandenburg & William J. Faller & Todd W. Ridky & Marco Demaria, 2022. "Targeting anti-apoptotic pathways eliminates senescent melanocytes and leads to nevi regression," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    17. Yuling Xiao & Jiang Chen & Hui Zhou & Xiaodong Zeng & Zhiping Ruan & Zhangya Pu & Xingya Jiang & Aya Matsui & Lingling Zhu & Zohreh Amoozgar & Dean Shuailin Chen & Xiangfei Han & Dan G. Duda & Jinjun , 2022. "Combining p53 mRNA nanotherapy with immune checkpoint blockade reprograms the immune microenvironment for effective cancer therapy," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    18. Mei Zhao & Tianxiao Wang & Frederico O. Gleber-Netto & Zhen Chen & Daniel J. McGrail & Javier A. Gomez & Wutong Ju & Mayur A. Gadhikar & Wencai Ma & Li Shen & Qi Wang & Ximing Tang & Sen Pathak & Mari, 2024. "Mutant p53 gains oncogenic functions through a chromosomal instability-induced cytosolic DNA response," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    19. Sascha Schäuble & Karolin Klement & Shiva Marthandan & Sandra Münch & Ines Heiland & Stefan Schuster & Peter Hemmerich & Stephan Diekmann, 2012. "Quantitative Model of Cell Cycle Arrest and Cellular Senescence in Primary Human Fibroblasts," PLOS ONE, Public Library of Science, vol. 7(8), pages 1-14, August.
    20. Leighton H. Daigh & Debarya Saha & David L. Rosenthal & Katherine R. Ferrick & Tobias Meyer, 2024. "Uncoupling of mTORC1 from E2F activity maintains DNA damage and senescence," Nature Communications, Nature, vol. 15(1), pages 1-16, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:plo:pbio00:0060301. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: plosbiology (email available below). General contact details of provider: https://journals.plos.org/plosbiology/ .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.