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The dynamic nature of senescence in cancer

Abstract

Cellular senescence is implicated in physiological and pathological processes spanning development, wound healing, age-related decline in organ functions and cancer. Here, we discuss cell-autonomous and non-cell-autonomous properties of senescence in the context of tumour formation and anticancer therapy, and characterize these properties, such as reprogramming into stemness, tissue remodelling and immune crosstalk, as far more dynamic than suggested by the common view of senescence as an irreversible, static condition.

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Fig. 1: Global and focal chromatin remodelling in senescence.
Fig. 2: Cytoplasmic deregulation of proteostasis and secretion.
Fig. 3: Environmental crosstalk following senescence induction by oncogenes or anticancer therapy.
Fig. 4: The in vivo dynamics of various aspects of senescence in cancer control and progression.

References

  1. 1.

    Hayflick, L. & Moorhead, P. S. The limited in vitro lifetime of human diploid cell strains. Exp. Cell Res. 25, 585–621 (1961).

    CAS  PubMed  Google Scholar 

  2. 2.

    Childs, B. G., Durik, M., Baker, D. J. & van Deursen, J. M. Cellular senescence in aging and age-related disease: from mechanisms to therapy. Nat. Med. 21, 1424–1435 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Shay, J. W. Role of telomeres and telomerase in aging and cancer. Cancer Discov. 6, 584–593 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Kuilman, T., Michaloglou, C., Mooi, W. J. & Peeper, D. S. The essence of senescence. Genes Dev. 24, 2463–2479 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Kuilman, T. & Peeper, D. S. Senescence-messaging secretome: SMS-ing cellular stress. Nat. Rev. Cancer 9, 81–94 (2009).

    CAS  PubMed  Google Scholar 

  6. 6.

    Coppe, J. P., Desprez, P. Y., Krtolica, A. & Campisi, J. The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu. Rev. Pathol. 5, 99–118 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Perez-Mancera, P. A., Young, A. R. & Narita, M. Inside and out: the activities of senescence in cancer. Nat. Rev. Cancer 14, 547–558 (2014).

    CAS  PubMed  Google Scholar 

  8. 8.

    Chandra, T. et al. Global reorganization of the nuclear landscape in senescent cells. Cell Rep. 10, 471–483 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Dimri, G. P. et al. A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc. Natl Acad. Sci. USA 92, 9363–9367 (1995).

    CAS  PubMed  Google Scholar 

  10. 10.

    Serrano, M., Lin, A. W., McCurrach, M. E., Beach, D. & Lowe, S. W. Oncogenic Ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88, 593–602 (1997).

    CAS  PubMed  Google Scholar 

  11. 11.

    Narita, M. et al. Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence. Cell 113, 703–716 (2003).

    CAS  PubMed  Google Scholar 

  12. 12.

    Coppe, J. P. et al. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol. 6, 2853–2868 (2008).

    CAS  PubMed  Google Scholar 

  13. 13.

    Salama, R., Sadaie, M., Hoare, M. & Narita, M. Cellular senescence and its effector programs. Genes Dev. 28, 99–114 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Sharpless, N. E. & Sherr, C. J. Forging a signature of in vivo senescence. Nat. Rev. Cancer 15, 397–408 (2015).

    CAS  PubMed  Google Scholar 

  15. 15.

    Seshadri, T. & Campisi, J. Repression of c-fos transcription and an altered genetic program in senescent human fibroblasts. Science 247, 205–209 (1990).

    CAS  PubMed  Google Scholar 

  16. 16.

    Beausejour, C. M. et al. Reversal of human cellular senescence: roles of the p53 and p16 pathways. EMBO J. 22, 4212–4222 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Sage, J., Miller, A. L., Perez-Mancera, P. A., Wysocki, J. M. & Jacks, T. Acute mutation of retinoblastoma gene function is sufficient for cell cycle re-entry. Nature 424, 223–228 (2003).

    CAS  PubMed  Google Scholar 

  18. 18.

    Milanovic, M. et al. Senescence-associated reprogramming promotes cancer stemness. Nature 553, 96–100 (2018).

    CAS  PubMed  Google Scholar 

  19. 19.

    Yu, Y. et al. Targeting the senescence-overriding cooperative activity of structurally unrelated H3K9 demethylases in melanoma. Cancer Cell 33, 322–336 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Mosteiro, L. et al. Tissue damage and senescence provide critical signals for cellular reprogramming in vivo. Science 354, aaf4445 (2016).

    PubMed  Google Scholar 

  21. 21.

    Chiche, A. et al. Injury-induced senescence enables in vivo reprogramming in skeletal muscle. Cell Stem Cell 20, 407–414.e4 (2017).

    CAS  PubMed  Google Scholar 

  22. 22.

    Latella, L. et al. DNA damage signaling mediates the functional antagonism between replicative senescence and terminal muscle differentiation. Genes Dev. 31, 648–659 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Ritschka, B. et al. The senescence-associated secretory phenotype induces cellular plasticity and tissue regeneration. Genes Dev. 31, 172–183 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Giancotti, F. G. Mechanisms governing metastatic dormancy and reactivation. Cell 155, 750–764 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Sosa, M. S., Bragado, P. & Aguirre-Ghiso, J. A. Mechanisms of disseminated cancer cell dormancy: an awakening field. Nat. Rev. Cancer 14, 611–622 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26.

    De Cecco, M. et al. Genomes of replicatively senescent cells undergo global epigenetic changes leading to gene silencing and activation of transposable elements. Aging Cell 12, 247–256 (2013).

    PubMed  PubMed Central  Google Scholar 

  27. 27.

    Ivanov, A. et al. Lysosome-mediated processing of chromatin in senescence. J. Cell Biol. 202, 129–143 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Dou, Z. et al. Autophagy mediates degradation of nuclear lamina. Nature 527, 105–109 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Kang, C. et al. The DNA damage response induces inflammation and senescence by inhibiting autophagy of GATA4. Science 349, aaa5612 (2015).

    PubMed  PubMed Central  Google Scholar 

  30. 30.

    Dou, Z. et al. Cytoplasmic chromatin triggers inflammation in senescence and cancer. Nature 550, 402–406 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Gluck, S. et al. Innate immune sensing of cytosolic chromatin fragments through cGAS promotes senescence. Nat. Cell Biol. 19, 1061–1070 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Salmina, K. et al. Nucleolar aggresomes mediate release of pericentric heterochromatin and nuclear destruction of genotoxically treated cancer cells. Nucleus 8, 205–221 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Yang, H., Wang, H., Ren, J., Chen, Q. & Chen, Z. J. cGAS is essential for cellular senescence. Proc. Natl Acad. Sci. USA 114, E4612–E4620 (2017).

    CAS  PubMed  Google Scholar 

  34. 34.

    Di Micco, R. et al. Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature 444, 638–642 (2006).

    PubMed  Google Scholar 

  35. 35.

    Fumagalli, M. et al. Telomeric DNA damage is irreparable and causes persistent DNA-damage-response activation. Nat. Cell Biol. 14, 355–365 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Hoare, M. et al. NOTCH1 mediates a switch between two distinct secretomes during senescence. Nat. Cell Biol. 18, 979–992 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Schmitt, C. A. The persistent dynamic secrets of senescence. Nat. Cell Biol. 18, 913–915 (2016).

    CAS  PubMed  Google Scholar 

  38. 38.

    Quijano, C. et al. Oncogene-induced senescence results in marked metabolic and bioenergetic alterations. Cell Cycle 11, 1383–1392 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Dorr, J. R. et al. Synthetic lethal metabolic targeting of cellular senescence in cancer therapy. Nature 501, 421–425 (2013).

    PubMed  Google Scholar 

  40. 40.

    Kaplon, J. et al. A key role for mitochondrial gatekeeper pyruvate dehydrogenase in oncogene-induced senescence. Nature 498, 109–112 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Kang, T. W. et al. Senescence surveillance of pre-malignant hepatocytes limits liver cancer development. Nature 479, 547–551 (2011).

    CAS  PubMed  Google Scholar 

  42. 42.

    Ohtani, N. et al. Opposing effects of Ets and Id proteins on p16INK4a expression during cellular senescence. Nature 409, 1067–1070 (2001).

    CAS  PubMed  Google Scholar 

  43. 43.

    Lin, A. W. et al. Premature senescence involving p53 and p16 is activated in response to constitutive MEK/MAPK mitogenic signaling. Genes Dev. 12, 3008–3019 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Bartkova, J. et al. Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature 444, 633–637 (2006).

    CAS  PubMed  Google Scholar 

  45. 45.

    Ferbeyre, G. et al. PML is induced by oncogenic Ras and promotes premature senescence. Genes Dev. 14, 2015–2027 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Zhang, R. et al. Formation of MacroH2A-containing senescence-associated heterochromatin foci and senescence driven by ASF1A and HIRA. Dev. Cell 8, 19–30 (2005).

    CAS  PubMed  Google Scholar 

  47. 47.

    Narita, M. et al. A novel role for high-mobility group a proteins in cellular senescence and heterochromatin formation. Cell 126, 503–514 (2006).

    CAS  PubMed  Google Scholar 

  48. 48.

    Ye, X. et al. Definition of pRB- and p53-dependent and -independent steps in HIRA/ASF1A-mediated formation of senescence-associated heterochromatin foci. Mol. Cell. Biol. 27, 2452–2465 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Chandra, T. et al. Independence of repressive histone marks and chromatin compaction during senescent heterochromatic layer formation. Mol. Cell 47, 203–214 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Sadaie, M. et al. Redistribution of the lamin B1 genomic binding profile affects rearrangement of heterochromatic domains and SAHF formation during senescence. Genes Dev. 27, 1800–1808 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Shah, P. P. et al. Lamin B1 depletion in senescent cells triggers large-scale changes in gene expression and the chromatin landscape. Genes Dev. 27, 1787–1799 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Rai, T. S. et al. HIRA orchestrates a dynamic chromatin landscape in senescence and is required for suppression of neoplasia. Genes Dev. 28, 2712–2725 (2014).

    PubMed  PubMed Central  Google Scholar 

  53. 53.

    Tasdemir, N. et al. BRD4 connects enhancer remodeling to senescence immune surveillance. Cancer Discov. 6, 612–629 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54.

    Hewitt, G. et al. Telomeres are favoured targets of a persistent DNA damage response in ageing and stress-induced senescence. Nat. Commun. 3, 708 (2012).

    PubMed  PubMed Central  Google Scholar 

  55. 55.

    Suram, A. et al. Oncogene-induced telomere dysfunction enforces cellular senescence in human cancer precursor lesions. EMBO J. 31, 2839–2851 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Rodier, F. et al. DNA-SCARS: distinct nuclear structures that sustain damage-induced senescence growth arrest and inflammatory cytokine secretion. J. Cell Sci. 124, 68–81 (2011).

    CAS  PubMed  Google Scholar 

  57. 57.

    Sulli, G., Di Micco, R. & d’Adda di Fagagna, F. Crosstalk between chromatin state and DNA damage response in cellular senescence and cancer. Nat. Rev. Cancer 12, 709–720 (2012).

    CAS  PubMed  Google Scholar 

  58. 58.

    Rapisarda, V. et al. Integrin β3 regulates cellular senescence by activating the TGF-β pathway. Cell Rep. 18, 2480–2493 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. 59.

    Ito, T., Teo, Y. V., Evans, S. A., Neretti, N. & Sedivy, J. M. Regulation of cellular senescence by Polycomb chromatin modifiers through distinct DNA damage- and histone methylation-dependent pathways. Cell Rep. 22, 3480–3492 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60.

    Acosta, J. C. et al. Chemokine signaling via the CXCR2 receptor reinforces senescence. Cell 133, 1006–1018 (2008).

    CAS  PubMed  Google Scholar 

  61. 61.

    Kuilman, T. et al. Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network. Cell 133, 1019–1031 (2008).

    CAS  PubMed  Google Scholar 

  62. 62.

    Chien, Y. et al. Control of the senescence-associated secretory phenotype by NF-κB promotes senescence and enhances chemosensitivity. Genes Dev. 25, 2125–2136 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63.

    Jing, H. et al. Opposing roles of NF-κB in anti-cancer treatment outcome unveiled by cross-species investigations. Genes Dev. 25, 2137–2146 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64.

    Shimi, T. et al. The role of nuclear lamin B1 in cell proliferation and senescence. Genes Dev. 25, 2579–2593 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65.

    Takahashi, A. et al. Exosomes maintain cellular homeostasis by excreting harmful DNA from cells. Nat. Commun. 8, 15287 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66.

    Ahn, J., Gutman, D., Saijo, S. & Barber, G. N. STING manifests self DNA-dependent inflammatory disease. Proc. Natl Acad. Sci. USA 109, 19386–19391 (2012).

    CAS  PubMed  Google Scholar 

  67. 67.

    Ablasser, A. et al. cGAS produces a 2′-5′-linked cyclic dinucleotide second messenger that activates STING. Nature 498, 380–384 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68.

    Xue, W. et al. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature 445, 656–660 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69.

    Chuprin, A. et al. Cell fusion induced by ERVWE1 or measles virus causes cellular senescence. Genes Dev. 27, 2356–2366 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70.

    Biran, A. et al. Senescent cells communicate via intercellular protein transfer. Genes Dev. 29, 791–802 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. 71.

    Krtolica, A., Parrinello, S., Lockett, S., Desprez, P. Y. & Campisi, J. Senescent fibroblasts promote epithelial cell growth and tumorigenesis: a link between cancer and aging. Proc. Natl Acad. Sci. USA 98, 12072–12077 (2001).

    CAS  PubMed  Google Scholar 

  72. 72.

    Ohanna, M. et al. Senescent cells develop a PARP-1 and nuclear factor-κB-associated secretome (PNAS). Genes Dev. 25, 1245–1261 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73.

    Lasry, A. & Ben-Neriah, Y. Senescence-associated inflammatory responses: aging and cancer perspectives. Trends Immunol. 36, 217–228 (2015).

    CAS  PubMed  Google Scholar 

  74. 74.

    Davalos, A. R. et al. p53-dependent release of alarmin HMGB1 is a central mediator of senescent phenotypes. J. Cell Biol. 201, 613–629 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. 75.

    Kortlever, R. M., Higgins, P. J. & Bernards, R. Plasminogen activator inhibitor-1 is a critical downstream target of p53 in the induction of replicative senescence. Nat. Cell Biol. 8, 877–884 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76.

    Acosta, J. C. et al. A complex secretory program orchestrated by the inflammasome controls paracrine senescence. Nat. Cell Biol. 15, 978–990 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 77.

    Eggert, T. et al. Distinct functions of senescence-associated immune responses in liver tumor surveillance and tumor progression. Cancer Cell 30, 533–547 (2016).

    CAS  PubMed  Google Scholar 

  78. 78.

    Reimann, M. et al. Tumor stroma-derived TGF-β limits Myc-driven lymphomagenesis via Suv39h1-dependent senescence. Cancer Cell 17, 262–272 (2010).

    CAS  PubMed  Google Scholar 

  79. 79.

    van Riggelen, J. et al. The interaction between Myc and Miz1 is required to antagonize TGFβ-dependent autocrine signaling during lymphoma formation and maintenance. Genes Dev. 24, 1281–1294 (2010).

    PubMed  PubMed Central  Google Scholar 

  80. 80.

    Braumuller, H. et al. T-helper-1-cell cytokines drive cancer into senescence. Nature 494, 361–365 (2013).

    PubMed  Google Scholar 

  81. 81.

    Wang, L. et al. High-throughput functional genetic and compound screens identify targets for senescence induction in cancer. Cell Rep. 21, 773–783 (2017).

    CAS  PubMed  Google Scholar 

  82. 82.

    Debacq-Chainiaux, F., Erusalimsky, J. D., Campisi, J. & Toussaint, O. Protocols to detect senescence-associated β-galactosidase (SA-βgal) activity, a biomarker of senescent cells in culture and in vivo. Nat. Protoc. 4, 1798–1806 (2009).

    CAS  PubMed  Google Scholar 

  83. 83.

    Bash, J. et al. Rel/NF-κB can trigger the Notch signaling pathway by inducing the expression of Jagged1, a ligand for Notch receptors. EMBO J. 18, 2803–2811 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84.

    Schwarzer, R., Dorken, B. & Jundt, F. Notch is an essential upstream regulator of NF-κB and is relevant for survival of Hodgkin and Reed-Sternberg cells. Leukemia 26, 806–813 (2012).

    CAS  PubMed  Google Scholar 

  85. 85.

    Pribluda, A. et al. A senescence-inflammatory switch from cancer-inhibitory to cancer-promoting mechanism. Cancer Cell 24, 242–256 (2013).

    CAS  PubMed  Google Scholar 

  86. 86.

    Schwitalla, S. et al. Loss of p53 in enterocytes generates an inflammatory microenvironment enabling invasion and lymph node metastasis of carcinogen-induced colorectal tumors. Cancer Cell 23, 93–106 (2013).

    CAS  PubMed  Google Scholar 

  87. 87.

    Hernandez-Segura, A. et al. Unmasking transcriptional heterogeneity in senescent cells. Curr. Biol. 27, 2652–2660.e4 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. 88.

    Toso, A. et al. Enhancing chemotherapy efficacy in Pten-deficient prostate tumors by activating the senescence-associated antitumor immunity. Cell Rep. 9, 75–89 (2014).

    CAS  PubMed  Google Scholar 

  89. 89.

    Schapiro, D. et al. histoCAT: analysis of cell phenotypes and interactions in multiplex image cytometry data. Nat Methods 14, 873–876 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90.

    Georgilis, A. et al. PTBP1-mediated alternative splicing regulates the inflammatory secretome and the pro-tumorigenic effects of senescent cells. Cancer Cell 34, 85–102.e9 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. 91.

    Zhu, J. et al. Genome-wide chromatin state transitions associated with developmental and environmental cues. Cell 152, 642–654 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. 92.

    Munoz-Espin, D. et al. Programmed cell senescence during mammalian embryonic development. Cell 155, 1104–1118 (2013).

    CAS  PubMed  Google Scholar 

  93. 93.

    Storer, M. et al. Senescence is a developmental mechanism that contributes to embryonic growth and patterning. Cell 155, 1119–1130 (2013).

    CAS  PubMed  Google Scholar 

  94. 94.

    Demaria, M. et al. An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA. Dev. Cell 31, 722–733 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. 95.

    Michaloglou, C. et al. BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature 436, 720–724 (2005).

    CAS  PubMed  Google Scholar 

  96. 96.

    Haugstetter, A. M. et al. Cellular senescence predicts treatment outcome in metastasised colorectal cancer. Br. J. Cancer 103, 505–509 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. 97.

    Tamayo-Orrego, L. et al. Evasion of cell senescence leads to medulloblastoma progression. Cell Rep. 14, 2925–2937 (2016).

    CAS  PubMed  Google Scholar 

  98. 98.

    Banito, A. et al. Senescence impairs successful reprogramming to pluripotent stem cells. Genes Dev. 23, 2134–2139 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. 99.

    Hong, H. et al. Suppression of induced pluripotent stem cell generation by the p53–p21 pathway. Nature 460, 1132–1135 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100.

    Kawamura, T. et al. Linking the p53 tumour suppressor pathway to somatic cell reprogramming. Nature 460, 1140–1144 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. 101.

    Li, H. et al. The Ink4/Arf locus is a barrier for iPS cell reprogramming. Nature 460, 1136–1139 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. 102.

    Marion, R. M. et al. A p53-mediated DNA damage response limits reprogramming to ensure iPS cell genomic integrity. Nature 460, 1149–1153 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. 103.

    Utikal, J. et al. Immortalization eliminates a roadblock during cellular reprogramming into iPS cells. Nature 460, 1145–1148 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. 104.

    Cruickshanks, H. A. et al. Senescent cells harbour features of the cancer epigenome. Nat. Cell Biol. 15, 1495–1506 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. 105.

    Waddington, C. H. The Strategy of the Genes: a Discussion of Some Aspects of Theoretical Biology (Allen & Unwin, London, 1957).

  106. 106.

    Wajapeyee, N., Serra, R. W., Zhu, X., Mahalingam, M. & Green, M. R. Oncogenic BRAF induces senescence and apoptosis through pathways mediated by the secreted protein IGFBP7. Cell 132, 363–374 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. 107.

    Neves, J., Demaria, M., Campisi, J. & Jasper, H. Of flies, mice, and men: evolutionarily conserved tissue damage responses and aging. Dev. Cell 32, 9–18 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. 108.

    Aarts, M. et al. Coupling shRNA screens with single-cell RNA-seq identifies a dual role for mTOR in reprogramming-induced senescence. Genes Dev. 31, 2085–2098 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. 109.

    Schmitt, C. A. et al. A senescence program controlled by p53 and p16INK4a contributes to the outcome of cancer therapy. Cell 109, 335–346 (2002).

    CAS  PubMed  Google Scholar 

  110. 110.

    Braig, M. et al. Oncogene-induced senescence as an initial barrier in lymphoma development. Nature 436, 660–665 (2005).

    CAS  PubMed  Google Scholar 

  111. 111.

    Collado, M. et al. Tumour biology: senescence in premalignant tumours. Nature 436, 642 (2005).

    CAS  PubMed  Google Scholar 

  112. 112.

    Lazzerini Denchi, E., Attwooll, C., Pasini, D. & Helin, K. Deregulated E2F activity induces hyperplasia and senescence-like features in the mouse pituitary gland. Mol. Cell. Biol. 25, 2660–2672 (2005).

    PubMed  Google Scholar 

  113. 113.

    Baker, D. J. et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 479, 232–236 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. 114.

    Baker, D. J. et al. Naturally occurring p16Ink4a-positive cells shorten healthy lifespan. Nature 530, 184–189 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. 115.

    Demaria, M. et al. Cellular senescence promotes adverse effects of chemotherapy and cancer relapse. Cancer Discov. 7, 165–176 (2017).

    CAS  PubMed  Google Scholar 

  116. 116.

    Farr, J. N. et al. Targeting cellular senescence prevents age-related bone loss in mice. Nat. Med. 23, 1072–1079 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. 117.

    Jeon, O. H. et al. Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment. Nat. Med. 23, 775–781 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. 118.

    Xu, M. et al. JAK inhibition alleviates the cellular senescence-associated secretory phenotype and frailty in old age. Proc. Natl Acad. Sci. USA 112, E6301–E6310 (2015).

    CAS  PubMed  Google Scholar 

  119. 119.

    Zhu, Y. et al. The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell 14, 644–658 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. 120.

    Zhu, Y. et al. New agents that target senescent cells: the flavone, fisetin, and the BCL-XL inhibitors, A1331852 and A1155463. Aging (Albany NY) 9, 955–963 (2017).

    Google Scholar 

  121. 121.

    Schmitt, C. A. UnSASPing senescence: unmasking tumor suppression? Cancer Cell 34, 6–8 (2018).

    CAS  PubMed  Google Scholar 

  122. 122.

    Nardella, C., Clohessy, J. G., Alimonti, A. & Pandolfi, P. P. Pro-senescence therapy for cancer treatment. Nat. Rev. Cancer 11, 503–511 (2011).

    CAS  PubMed  Google Scholar 

  123. 123.

    Kirkland, J. L. & Tchkonia, T. Cellular senescence: a translational perspective. EBioMedicine 21, 21–28 (2017).

    PubMed  PubMed Central  Google Scholar 

  124. 124.

    Narita, M. et al. Spatial coupling of mTOR and autophagy augments secretory phenotypes. Science 332, 966–970 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. 125.

    Young, A. R. et al. Autophagy mediates the mitotic senescence transition. Genes Dev. 23, 798–803 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. 126.

    Lehmann, B. D. et al. Senescence-associated exosome release from human prostate cancer cells. Cancer Res. 68, 7864–7871 (2008).

    CAS  PubMed  Google Scholar 

  127. 127.

    Schafer, M. J. et al. Cellular senescence mediates fibrotic pulmonary disease. Nat. Commun. 8, 14532 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by grants to C.A.S. from the Deutsche Forschungsgemeinschaft (SCHM 1633/9-1 and SCHM 1633/11-1), by the Helmholtz Alliance ‘Preclinical Comprehensive Cancer Center’ grant (no. HA-305) from the Helmholtz Association and by the Deutsche Krebshilfe (grant no. 110678). This work was further made possible by the Berlin School of Integrative Oncology (BSIO) graduate program, funded within the German Excellence Initiative and the German Cancer Consortium (GCC), to S.L. and C.A.S.

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Correspondence to Clemens A. Schmitt.

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Lee, S., Schmitt, C.A. The dynamic nature of senescence in cancer. Nat Cell Biol 21, 94–101 (2019). https://doi.org/10.1038/s41556-018-0249-2

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