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Outcompeting cancer

Nature Reviews Cancer volume 20, pages 187–198 (2020)Cite this article

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A Publisher Correction to this article was published on 14 April 2020

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Abstract

The tumour microenvironment plays a critical role in determining tumour fate. Within that environment, and indeed throughout epithelial tissues, cells experience competition with their neighbours, with those less fit being eliminated by fitter adjacent cells. Herein we discuss evidence suggesting that mutations in cancer cells may be selected for their ability to exploit cell competition to kill neighbouring host cells, thereby facilitating tumour expansion. In some instances, cell competition may help host tissues to defend against cancer, by removing neoplastic and aneuploid cells. Cancer risk factors, such as high-sugar or high-fat diet and inflammation, impact cell competition-based host defences, suggesting that their effect on tumour risk may in part be accounted for by their influence on cell competition. We propose that interventions aimed at modifying the strength and direction of cell competition could induce cancer cell killing and form the basis for novel anticancer therapies.

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Fig. 1: Cell competition.
Fig. 2: Cell competition drives tumorigenesis.
Fig. 3: Intrinsic tumour-suppressive cell competition.
Fig. 4: The microenvironment modulates cell competition and tumour growth.
Fig. 5: Exploiting cell competition as an anticancer therapy.

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References

  1. Kastan, M. B. & Bartek, J. Cell-cycle checkpoints and cancer. Nature 432, 316–323 (2004).

    Article  CAS  PubMed  Google Scholar 

  2. Massague, J. G1 cell-cycle control and cancer. Nature 432, 298–306 (2004).

    Article  CAS  PubMed  Google Scholar 

  3. Evan, G. I. & Vousden, K. H. Proliferation, cell cycle and apoptosis in cancer. Nature 411, 342–348 (2001).

    Article  CAS  PubMed  Google Scholar 

  4. Wagstaff, L. et al. Mechanical cell competition kills cells via induction of lethal p53 levels. Nat. Commun. 7, 11373 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Suijkerbuijk, S. J., Kolahgar, G., Kucinski, I. & Piddini, E. Cell competition drives the growth of intestinal adenomas in Drosophila. Curr. Biol. 26, 428–438 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Moreno, E. & Basler, K. dMyc transforms cells into super-competitors. Cell 117, 117–129 (2004).

    Article  CAS  PubMed  Google Scholar 

  7. de la Cova, C., Abril, M., Bellosta, P., Gallant, P. & Johnston, L. A. Drosophila myc regulates organ size by inducing cell competition. Cell 117, 107–116 (2004).

    Article  PubMed  Google Scholar 

  8. Brown, S. et al. Correction of aberrant growth preserves tissue homeostasis. Nature 548, 334–337 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Hogan, C. et al. Characterization of the interface between normal and transformed epithelial cells. Nat. Cell Biol. 11, 460–467 (2009).

    Article  CAS  PubMed  Google Scholar 

  10. Kajita, M. et al. Filamin acts as a key regulator in epithelial defence against transformed cells. Nat. Commun. 5, 4428 (2014).

    Article  CAS  PubMed  Google Scholar 

  11. Ohoka, A. et al. EPLIN is a crucial regulator for extrusion of RasV12-transformed cells. J. Cell Sci. 128, 781–789 (2015).

    CAS  PubMed  Google Scholar 

  12. Eisenhoffer, G. T. et al. Crowding induces live cell extrusion to maintain homeostatic cell numbers in epithelia. Nature 484, 546–549 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Ohsawa, S., Vaughen, J. & Igaki, T. Cell extrusion: a stress-responsive force for good or evil in epithelial homeostasis. Dev. Cell 44, 284–296 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Marinari, E. et al. Live-cell delamination counterbalances epithelial growth to limit tissue overcrowding. Nature 484, 542–545 (2012).

    Article  CAS  PubMed  Google Scholar 

  15. Ellis, S. J. et al. Distinct modes of cell competition shape mammalian tissue morphogenesis. Nature 569, 497–502 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Liu, N. et al. Stem cell competition orchestrates skin homeostasis and ageing. Nature 568, 344–350 (2019).

    Article  CAS  PubMed  Google Scholar 

  17. Kolahgar, G. et al. Cell competition modifies adult stem cell and tissue population dynamics in a JAK-STAT-dependent manner. Dev. Cell 34, 297–309 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Watanabe, H. et al. Mutant p53-expressing cells undergo necroptosis via cell competition with the neighboring normal epithelial cells. Cell Rep. 23, 3721–3729 (2018).

    Article  CAS  PubMed  Google Scholar 

  19. Li, W. & Baker, N. E. Engulfment is required for cell competition. Cell 129, 1215–1225 (2007).

    Article  CAS  PubMed  Google Scholar 

  20. Ohsawa, S. et al. Elimination of oncogenic neighbors by JNK-mediated engulfment in Drosophila. Dev. Cell 20, 315–328 (2011).

    Article  CAS  PubMed  Google Scholar 

  21. Sun, Q. et al. Competition between human cells by entosis. Cell Res. 24, 1299–1310 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Hamann, J. C. et al. Entosis is induced by glucose starvation. Cell Rep. 20, 201–210 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Morata, G. & Ripoll, P. Minutes: mutants of Drosophila autonomously affecting cell division rate. Dev. Biol. 42, 211–221 (1975).

    Article  CAS  PubMed  Google Scholar 

  24. Simpson, P. Parameters of cell competition in the compartments of the wing disc of Drosophila. Dev. Biol. 69, 182–193 (1979).

    Article  CAS  PubMed  Google Scholar 

  25. Simpson, P. & Morata, G. Differential mitotic rates and patterns of growth in compartments in the Drosophila wing. Dev. Biol. 85, 299–308 (1981).

    Article  CAS  PubMed  Google Scholar 

  26. Oliver, E. R., Saunders, T. L., Tarle, S. A. & Glaser, T. Ribosomal protein L24 defect in belly spot and tail (Bst), a mouse Minute. Development 131, 3907–3920 (2004).

    Article  CAS  PubMed  Google Scholar 

  27. Baker, N. E. Mechanisms of cell competition emerging from Drosophila studies. Curr. Opin. Cell Biol. 48, 40–46 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Di Gregorio, A., Bowling, S. & Rodriguez, T. A. Cell competition and its role in the regulation of cell fitness from development to cancer. Dev. Cell 38, 621–634 (2016).

    Article  PubMed  CAS  Google Scholar 

  29. Amoyel, M. & Bach, E. A. Cell competition: how to eliminate your neighbours. Development 141, 988–1000 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Gutierrez-Martinez, A., Guinevere Sew, W. Q., Molano-Fernandez, M., Carretero-Junquera, M. & Herranz, H. Mechanisms of oncogenic cell competition - paths of victory. Semin. Cancer Biol. https://doi.org/10.1016/j.semcancer.2019.05.015 (2019).

  31. Maruyama, T. & Fujita, Y. Cell competition in mammals - novel homeostatic machinery for embryonic development and cancer prevention. Curr. Opin. Cell Biol. 48, 106–112 (2017).

    Article  CAS  PubMed  Google Scholar 

  32. Claveria, C. & Torres, M. Cell competition: mechanisms and physiological roles. Annu. Rev. Cell Dev. Biol. 32, 411–439 (2016).

    Article  CAS  PubMed  Google Scholar 

  33. Vincent, J. P., Fletcher, A. G. & Baena-Lopez, L. A. Mechanisms and mechanics of cell competition in epithelia. Nat. Rev. Mol. Cell Biol. 14, 581–591 (2013).

    Article  CAS  PubMed  Google Scholar 

  34. Neto-Silva, R. M., de Beco, S. & Johnston, L. A. Evidence for a growth-stabilizing regulatory feedback mechanism between Myc and Yorkie, the Drosophila homolog of Yap. Dev. Cell 19, 507–520 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Johnston, L. A., Prober, D. A., Edgar, B. A., Eisenman, R. N. & Gallant, P. Drosophila myc regulates cellular growth during development. Cell 98, 779–790 (1999).

    Article  CAS  PubMed  Google Scholar 

  36. Norman, M. et al. Loss of Scribble causes cell competition in mammalian cells. J. Cell Sci. 125, 59–66 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Igaki, T., Pagliarini, R. A. & Xu, T. Loss of cell polarity drives tumor growth and invasion through JNK activation in Drosophila. Curr. Biol. 16, 1139–1146 (2006).

    Article  CAS  PubMed  Google Scholar 

  38. Brumby, A. M. & Richardson, H. E. Scribble mutants cooperate with oncogenic Ras or Notch to cause neoplastic overgrowth in Drosophila. EMBO J. 22, 5769–5779 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Moitrier, S. et al. Collective stresses drive competition between monolayers of normal and Ras-transformed cells. Soft Matter 15, 537–545 (2019).

    Article  CAS  PubMed  Google Scholar 

  40. Kajita, M. et al. Interaction with surrounding normal epithelial cells influences signalling pathways and behaviour of Src-transformed cells. J. Cell Sci. 123, 171–180 (2010).

    Article  CAS  PubMed  Google Scholar 

  41. Takagi, M. et al. Accumulation of the myosin-II-spectrin complex plays a positive role in apical extrusion of Src-transformed epithelial cells. Genes Cell 23, 974–981 (2018).

    Article  CAS  Google Scholar 

  42. Tamori, Y. et al. Involvement of Lgl and Mahjong/VprBP in cell competition. PLoS Biol. 8, e1000422 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Ballesteros-Arias, L., Saavedra, V. & Morata, G. Cell competition may function either as tumour-suppressing or as tumour-stimulating factor in Drosophila. Oncogene 33, 4377–4384 (2013).

    Article  PubMed  CAS  Google Scholar 

  44. Rodrigues, A. B. et al. Activated STAT regulates growth and induces competitive interactions independently of Myc, Yorkie, Wingless and ribosome biogenesis. Development 139, 4051–4061 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Vincent, J. P., Kolahgar, G., Gagliardi, M. & Piddini, E. Steep differences in wingless signaling trigger Myc-independent competitive cell interactions. Dev. Cell 21, 366–374 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Bondar, T. & Medzhitov, R. p53-mediated hematopoietic stem and progenitor cell competition. Cell Stem Cell 6, 309–322 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Marusyk, A., Porter, C. C., Zaberezhnyy, V. & DeGregori, J. Irradiation selects for p53-deficient hematopoietic progenitors. PLOS Biol. 8, e1000324 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Chen, C. L., Schroeder, M. C., Kango-Singh, M., Tao, C. & Halder, G. Tumor suppression by cell competition through regulation of the Hippo pathway. Proc. Natl Acad. Sci. USA 109, 484–489 (2012).

    Article  CAS  PubMed  Google Scholar 

  49. Menendez, J., Perez-Garijo, A., Calleja, M. & Morata, G. A tumor-suppressing mechanism in Drosophila involving cell competition and the Hippo pathway. Proc. Natl Acad. Sci. USA 107, 14651–14656 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Tyler, D. M., Li, W., Zhuo, N., Pellock, B. & Baker, N. E. Genes affecting cell competition in Drosophila. Genetics 175, 643–657 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Moreno, E., Basler, K. & Morata, G. Cells compete for Decapentaplegic survival factor to prevent apoptosis in Drosophila wing development. Nature 416, 755–759 (2002).

    Article  CAS  PubMed  Google Scholar 

  52. Adachi-Yamada, T. & O'Connor, M. B. Morphogenetic apoptosis: a mechanism for correcting discontinuities in morphogen gradients. Dev. Biol. 251, 74–90 (2002).

    Article  CAS  PubMed  Google Scholar 

  53. Pinal, N., Calleja, M. & Morata, G. Pro-apoptotic and pro-proliferation functions of the JNK pathway of Drosophila: roles in cell competition, tumorigenesis and regeneration. Open Biol. 9, 180256 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Johnston, L. A. Socializing with MYC: cell competition in development and as a model for premalignant cancer. Cold Spring Harb. Perspect. Med. 4, a014274 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Baillon, L. & Basler, K. Reflections on cell competition. Semin. Cell Dev. Biol. 32, 137–144 (2014).

    Article  PubMed  Google Scholar 

  56. Valon, L. & Levayer, R. Dying under pressure: cellular characterisation and in vivo functions of cell death induced by compaction. Biol. Cell 111, 51–66 (2019).

    Article  PubMed  Google Scholar 

  57. Rhiner, C. et al. Flower forms an extracellular code that reveals the fitness of a cell to its neighbors in Drosophila. Dev. Cell 18, 985–998 (2010).

    Article  CAS  PubMed  Google Scholar 

  58. Alpar, L., Bergantinos, C. & Johnston, L. A. Spatially restricted regulation of Spätzle/Toll signaling during cell competition. Dev. Cell 46, 706–719 e705 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Meyer, S. N. et al. An ancient defense system eliminates unfit cells from developing tissues during cell competition. Science 346, 1258236 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Yamamoto, M., Ohsawa, S., Kunimasa, K. & Igaki, T. The ligand Sas and its receptor PTP10D drive tumour-suppressive cell competition. Nature 542, 246–250 (2017).

    Article  CAS  PubMed  Google Scholar 

  61. Germani, F., Hain, D., Sternlicht, D., Moreno, E. & Basler, K. The Toll pathway inhibits tissue growth and regulates cell fitness in an infection-dependent manner. Elife 7, https://doi.org/10.7554/eLife.39939 (2018).

  62. Kolahi, K. S. & Mofrad, M. R. Mechanotransduction: a major regulator of homeostasis and development. Wiley Interdiscip. Rev. Syst. Biol. Med. 2, 625–639 (2010).

    Article  CAS  PubMed  Google Scholar 

  63. Ingallina, E. et al. Mechanical cues control mutant p53 stability through a mevalonate-RhoA axis. Nat. Cell Biol. 20, 28–35 (2018).

    Article  CAS  PubMed  Google Scholar 

  64. Shraiman, B. I. Mechanical feedback as a possible regulator of tissue growth. Proc. Natl Acad. Sci. USA 102, 3318–3323 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Gudipaty, S. A., Conner, C. M., Rosenblatt, J. & Montell, D. J. Unconventional ways to live and die: cell death and survival in development, homeostasis, and disease. Annu. Rev. Cell Dev. Biol. 34, 311–332 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Wyatt, T. P. et al. Emergence of homeostatic epithelial packing and stress dissipation through divisions oriented along the long cell axis. Proc. Natl Acad. Sci. USA 112, 5726–5731 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Curran, S. et al. Myosin II controls junction fluctuations to guide epithelial tissue ordering. Dev. Cell 43, 480–492 e486 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Khalilgharibi, N. et al. Stress relaxation in epithelial monolayers is controlled by the actomyosin cortex. Nat. Phys. 15, 839–847 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Levayer, R., Dupont, C. & Moreno, E. tissue crowding induces caspase-dependent competition for space. Curr. Biol. 26, 670–677 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Moreno, E., Valon, L., Levillayer, F. & Levayer, R. Competition for space induces cell elimination through compaction-driven ERK downregulation. Curr. Biol. 29, 23–34 e28 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Zhang, G. et al. p53 pathway is involved in cell competition during mouse embryogenesis. Proc. Natl Acad. Sci. USA 114, 498–503 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Dejosez, M., Ura, H., Brandt, V. L. & Zwaka, T. P. Safeguards for cell cooperation in mouse embryogenesis shown by genome-wide cheater screen. Science 341, 1511–1514 (2013).

    Article  CAS  PubMed  Google Scholar 

  73. Bowling, S. et al. P53 and mTOR signalling determine fitness selection through cell competition during early mouse embryonic development. Nat. Commun. 9, 1763 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Kon, S. et al. Cell competition with normal epithelial cells promotes apical extrusion of transformed cells through metabolic changes. Nat. Cell Biol. 19, 530–541 (2017).

    Article  CAS  PubMed  Google Scholar 

  75. Kalkat, M. et al. MYC deregulation in primary human cancers. Genes 8, 151 (2017).

    Article  PubMed Central  CAS  Google Scholar 

  76. Baker, N. E. & Li, W. Cell competition and its possible relation to cancer. Cancer Res. 68, 5505–5507 (2008).

    Article  CAS  PubMed  Google Scholar 

  77. Moreno, E. Is cell competition relevant to cancer? Nat. Rev. Cancer 8, 141–147 (2008).

    Article  CAS  PubMed  Google Scholar 

  78. Grifoni, D. & Bellosta, P. Drosophila Myc: a master regulator of cellular performance. Biochim. Biophys. Acta 1849, 570–581 (2015).

    Article  CAS  PubMed  Google Scholar 

  79. Paglia, S., Sollazzo, M., Di Giacomo, S., Strocchi, S. & Grifoni, D. Exploring MYC relevance to cancer biology from the perspective of cell competition. Semin. Cancer Biol. https://doi.org/10.1016/j.semcancer.2019.05.009 (2019).

  80. Claveria, C., Giovinazzo, G., Sierra, R. & Torres, M. Myc-driven endogenous cell competition in the early mammalian embryo. Nature 500, 39–44 (2013).

    Article  CAS  PubMed  Google Scholar 

  81. Sancho, M. et al. Competitive interactions eliminate unfit embryonic stem cells at the onset of differentiation. Dev. Cell 26, 19–30 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Villa Del Campo, C., Claveria, C., Sierra, R. & Torres, M. Cell competition promotes phenotypically silent cardiomyocyte replacement in the mammalian heart. Cell Rep. 8, 1741–1751 (2014).

    Article  CAS  PubMed  Google Scholar 

  83. Ziosi, M. et al. dMyc functions downstream of Yorkie to promote the supercompetitive behavior of hippo pathway mutant cells. PLOS Genet. 6, e1001140 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  84. Eichenlaub, T., Cohen, S. M. & Herranz, H. Cell competition drives the formation of metastatic tumors in a Drosophila model of epithelial tumor formation. Curr. Biol. 26, 419–427 (2016).

    Article  CAS  PubMed  Google Scholar 

  85. Patel, P. H., Dutta, D. & Edgar, B. A. Niche appropriation by Drosophila intestinal stem cell tumours. Nat. Cell Biol. 17, 1182–1192 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Alcolea, M. P. & Jones, P. H. Cell competition: winning out by losing notch. Cell Cycle 14, 9–17 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Schroeder, M. C., Chen, C. L., Gajewski, K. & Halder, G. A non-cell-autonomous tumor suppressor role for Stat in eliminating oncogenic scribble cells. Oncogene 32, 4471–4479 (2013).

    Article  CAS  PubMed  Google Scholar 

  88. Moya, I. M. & Halder, G. Hippo-YAP/TAZ signalling in organ regeneration and regenerative medicine. Nat. Rev. Mol. Cell Biol. 20, 211–226 (2019).

    Article  CAS  PubMed  Google Scholar 

  89. Harvey, K. F., Zhang, X. & Thomas, D. M. The Hippo pathway and human cancer. Nat. Rev. Cancer 13, 246–257 (2013).

    Article  CAS  PubMed  Google Scholar 

  90. Liu, Z. et al. Differential YAP expression in glioma cells induces cell competition and promotes tumorigenesis. J. Cell Sci. 132, https://doi.org/10.1242/jcs.225714 (2019).

  91. Zhan, T., Rindtorff, N. & Boutros, M. Wnt signaling in cancer. Oncogene 36, 1461–1473 (2017).

    Article  CAS  PubMed  Google Scholar 

  92. Groner, B. & von Manstein, V. Jak Stat signaling and cancer: opportunities, benefits and side effects of targeted inhibition. Mol. Cell Endocrinol. 451, 1–14 (2017).

    Article  CAS  PubMed  Google Scholar 

  93. Ryoo, H. D., Gorenc, T. & Steller, H. Apoptotic cells can induce compensatory cell proliferation through the JNK and the Wingless signaling pathways. Dev. Cell 7, 491–501 (2004).

    Article  CAS  PubMed  Google Scholar 

  94. Perez, E., Lindblad, J. L. & Bergmann, A. Tumor-promoting function of apoptotic caspases by an amplification loop involving ROS, macrophages and JNK in Drosophila. Elife 6, https://doi.org/10.7554/eLife.26747 (2017).

  95. Tannapfel, A. et al. Apoptosis, proliferation, bax, bcl-2 and p53 status prior to and after preoperative radiochemotherapy for locally advanced rectal cancer. Int. J. Radiat. Oncol. Biol. Phys. 41, 585–591 (1998).

    Article  CAS  PubMed  Google Scholar 

  96. de Bruin, E. C. & Medema, J. P. Apoptosis and non-apoptotic deaths in cancer development and treatment response. Cancer Treat. Rev. 34, 737–749 (2008).

    Article  PubMed  Google Scholar 

  97. Hiraoka, N. et al. Tumour necrosis is a postoperative prognostic marker for pancreatic cancer patients with a high interobserver reproducibility in histological evaluation. Br. J. Cancer 103, 1057–1065 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Zhang, L. & Shay, J. W. Multiple roles of APC and its therapeutic implications in colorectal cancer. J. Natl Cancer Inst. 8, 109 (2017).

    CAS  Google Scholar 

  99. Cordero, J., Vidal, M. & Sansom, O. APC as a master regulator of intestinal homeostasis and transformation: from flies to vertebrates. Cell Cycle 8, 2926–2931 (2009).

    Article  PubMed  Google Scholar 

  100. Cordero, J. B., Stefanatos, R. K., Myant, K., Vidal, M. & Sansom, O. J. Non-autonomous crosstalk between the Jak/Stat and Egfr pathways mediates Apc1-driven intestinal stem cell hyperplasia in the Drosophila adult midgut. Development 139, 4524–4535 (2012).

    Article  CAS  PubMed  Google Scholar 

  101. Bangi, E., Murgia, C., Teague, A. G., Sansom, O. J. & Cagan, R. L. Functional exploration of colorectal cancer genomes using Drosophila. Nat. Commun. 7, 13615 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Romano, G., Chagani, S. & Kwong, L. N. The path to metastatic mouse models of colorectal cancer. Oncogene 37, 2481–2489 (2018).

    Article  CAS  PubMed  Google Scholar 

  103. Snippert, H. J., Schepers, A. G., van Es, J. H., Simons, B. D. & Clevers, H. Biased competition between Lgr5 intestinal stem cells driven by oncogenic mutation induces clonal expansion. EMBO Rep. 15, 62–69 (2014).

    Article  CAS  PubMed  Google Scholar 

  104. Vermeulen, L. et al. Defining stem cell dynamics in models of intestinal tumor initiation. Science 342, 995–998 (2013).

    Article  CAS  PubMed  Google Scholar 

  105. Jonason, A. S. et al. Frequent clones of p53-mutated keratinocytes in normal human skin. Proc. Natl Acad. Sci. USA 93, 14025–14029 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Ling, G. et al. Persistent p53 mutations in single cells from normal human skin. Am. J. Pathol. 159, 1247–1253 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Martincorena, I. et al. Tumor evolution. High burden and pervasive positive selection of somatic mutations in normal human skin. Science 348, 880–886 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Lynch, M. D. et al. Spatial constraints govern competition of mutant clones in human epidermis. Nat. Commun. 8, 1119 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Klein, A. M., Brash, D. E., Jones, P. H. & Simons, B. D. Stochastic fate of p53-mutant epidermal progenitor cells is tilted toward proliferation by UV B during preneoplasia. Proc. Natl Acad. Sci. USA 107, 270–275 (2010).

    Article  CAS  PubMed  Google Scholar 

  110. Murai, K. et al. Epidermal tissue adapts to restrain progenitors carrying clonal p53 mutations. Cell Stem Cell 23, 687–699.e688 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Muller, P. A. & Vousden, K. H. Mutant p53 in cancer: new functions and therapeutic opportunities. Cancer Cell 25, 304–317 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Ziegler, A. et al. Sunburn and p53 in the onset of skin cancer. Nature 372, 773–776 (1994).

    Article  CAS  PubMed  Google Scholar 

  113. Nakazawa, H. et al. UV and skin cancer: specific p53 gene mutation in normal skin as a biologically relevant exposure measurement. Proc. Natl Acad. Sci. USA 91, 360–364 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Zhang, W. et al. UVB-induced apoptosis drives clonal expansion during skin tumor development. Carcinogenesis 26, 249–257 (2005).

    Article  CAS  PubMed  Google Scholar 

  115. Chao, D. L., Eck, J. T., Brash, D. E., Maley, C. C. & Luebeck, E. G. Preneoplastic lesion growth driven by the death of adjacent normal stem cells. Proc. Natl Acad. Sci. USA 105, 15034–15039 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Hall, P. A., M., P., Menage, H. D., Dover, R. & Lane, D. P. High levels of p53 protein in UV-irradiated normal human skin. Oncogene 8, 203–207 (1993).

    CAS  PubMed  Google Scholar 

  117. Bissell, M. J. & Hines, W. C. Why don't we get more cancer? A proposed role of the microenvironment in restraining cancer progression. Nat. Med. 17, 320–329 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Martins, V. C. et al. Cell competition is a tumour suppressor mechanism in the thymus. Nature 509, 465–470 (2014).

    Article  CAS  PubMed  Google Scholar 

  119. Igaki, T., Pastor-Pareja, J. C., Aonuma, H., Miura, M. & Xu, T. Intrinsic tumor suppression and epithelial maintenance by endocytic activation of Eiger/TNF signaling in Drosophila. Dev. Cell 16, 458–465 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Vidal, M., Larson, D. E. & Cagan, R. L. Csk-deficient boundary cells are eliminated from normal Drosophila epithelia by exclusion, migration, and apoptosis. Dev. Cell 10, 33–44 (2006).

    Article  CAS  PubMed  Google Scholar 

  121. Bilder, D., Li, M. & Perrimon, N. Cooperative regulation of cell polarity and growth by Drosophila tumor suppressors. Science 289, 113–116 (2000).

    Article  CAS  PubMed  Google Scholar 

  122. Zeitler, J., Hsu, C. P., Dionne, H. & Bilder, D. Domains controlling cell polarity and proliferation in the Drosophila tumor suppressor Scribble. J. Cell Biol. 167, 1137–1146 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Mechler, B. M., McGinnis, W. & Gehring, W. J. Molecular cloning of lethal(2)giant larvae, a recessive oncogene of Drosophila melanogaster. EMBO J. 4, 1551–1557 (1985).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Gateff, E. & Schneiderman, H. A. Developmental studies of a new mutant of Drosophila melanogaster-lethal malignant brain tumor. Am. Zool. 7, 760 (1967).

    Google Scholar 

  125. Okada, M., Nada, S., Yamanashi, Y., Yamamoto, T. & Nakagawa, H. CSK: a protein-tyrosine kinase involved in regulation of src family kinases. J. Biol. Chem. 266, 24249–24252 (1991).

    Article  CAS  PubMed  Google Scholar 

  126. Kajita, M. & Fujita, Y. EDAC: Epithelial defence against cancer-cell competition between normal and transformed epithelial cells in mammals. J. Biochem. 158, 15–23 (2015).

    Article  CAS  PubMed  Google Scholar 

  127. Chiba, T. et al. MDCK cells expressing constitutively active Yes-associated protein (YAP) undergo apical extrusion depending on neighboring cell status. Sci. Rep. 6, 28383 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Sasaki, A. et al. obesity suppresses cell-competition-mediated apical elimination of RasV12-transformed cells from epithelial tissues. Cell Rep. 23, 974–982 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Leung, C. T. & Brugge, J. S. Outgrowth of single oncogene-expressing cells from suppressive epithelial environments. Nature 482, 410–413 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Rajagopalan, H. & Lengauer, C. Aneuploidy and cancer. Nature 432, 338-341 (2004).

    Article  CAS  PubMed  Google Scholar 

  131. Chunduri, N. K. & Storchova, Z. The diverse consequences of aneuploidy. Nat. Cell Biol. 21, 54–62 (2019).

    Article  CAS  PubMed  Google Scholar 

  132. Negrini, S., Gorgoulis, V. G. & Halazonetis, T. D. Genomic instability–an evolving hallmark of cancer. Nat. Rev. Mol. Cell Biol. 11, 220–228 (2010).

    Article  CAS  PubMed  Google Scholar 

  133. Baker, N. E. Cell competition. Curr. Biol. 21, R11–R15 (2011).

    Article  CAS  PubMed  Google Scholar 

  134. Warner, J. R., Vilardell, J. & Sohn, J. H. Economics of ribosome biosynthesis. Cold Spring Harb. Symp. Quant. Biol. 66, 567–574 (2001).

    Article  CAS  PubMed  Google Scholar 

  135. Marygold, S. J. et al. The ribosomal protein genes and Minute loci of Drosophila melanogaster. Genome Biol. 8, R216 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  136. Mills, E.W. & Green R. Ribosomopathies: there’s strength in numbers. Science 358, eaan2755 (2017).

    Article  PubMed  CAS  Google Scholar 

  137. Ajore, R. et al. Deletion of ribosomal protein genes is a common vulnerability in human cancer, especially in concert with TP53 mutations. EMBO Mol. Med. 9, 498–507 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. McNamee, L. M. & Brodsky, M. H. p53-independent apoptosis limits DNA damage-induced aneuploidy. Genetics 182, 423–435 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Titen, S. W. & Golic, K. G. Telomere loss provokes multiple pathways to apoptosis and produces genomic instability in Drosophila melanogaster. Genetics 180, 1821–1832 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Bolton, H. et al. Mouse model of chromosome mosaicism reveals lineage-specific depletion of aneuploid cells and normal developmental potential. Nat. Commun. 7, 11165 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Pfau, S. J., Silberman, R. E., Knouse, K. A. & Amon, A. Aneuploidy impairs hematopoietic stem cell fitness and is selected against in regenerating tissues in vivo. Genes Dev. 30, 1395–1408 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Kucinski, I., Dinan, M., Kolahgar, G. & Piddini, E. Chronic activation of JNK JAK/STAT and oxidative stress signalling causes the loser cell status. Nat. Commun. 8, 136 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  143. Tamori, Y., Suzuki, E. & Deng, W. M. Epithelial tumors originate in tumor hotspots, a tissue-intrinsic microenvironment. PLOS Biol. 14, e1002537 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  144. Hirabayashi, S., Baranski, T. J. & Cagan, R. L. Transformed Drosophila cells evade diet-mediated insulin resistance through wingless signaling. Cell 154, 664–675 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Moi, P., C., K., Asunis, I., Cao, A. & Kan, Y. W. Isolation of NF-E2-related factor2 (Nrf2), a NF-E2-like basic leucine zipper transcriptional activator that binds to the tandem NF-E2/AP1 repeat of the f-globin locus control region. Proc. Natl Acad. Sci. USA 91, 9926–9930 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Itoh, Ken et al. An Nrf2/small Maf heterodimer mediates the induction of phase ii detoxifying enzyme genes through antioxidant response elements. Biochem. Biophys. Res. Commun. 236, 313–322 (1997).

    Article  CAS  PubMed  Google Scholar 

  147. Venugopal, R. & Jaiswal, A. K. Nrf1 and Nrf2 positively and c-Fos and Fra1 negatively regulate the human antioxidant response element-mediated expression of NAD(P)H:quinone oxidoreductase1 gene. Proc. Natl Acad. Sci. USA 93, 14960–14965 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Cook, J. A. et al. Oxidative stress, redox, and the tumor microenvironment. Semin. Radiat. Oncol. 14, 259–266 (2004).

    Article  PubMed  Google Scholar 

  149. Sosa, V. et al. Oxidative stress and cancer: an overview. Ageing Res. Rev. 12, 376–390 (2013).

    Article  CAS  PubMed  Google Scholar 

  150. Moloney, J. N. & Cotter, T. G. ROS signalling in the biology of cancer. Semin. Cell Dev. Biol. 80, 50–64 (2018).

    Article  CAS  PubMed  Google Scholar 

  151. Menegon, S., Columbano, A. & Giordano, S. The dual roles of NRF2 in cancer. Trends Mol. Med. 22, 578–593 (2016).

    Article  CAS  PubMed  Google Scholar 

  152. D'Autreaux, B. & Toledano, M. B. ROS as signalling molecules: mechanisms that generate specificity in ROS homeostasis. Nat. Rev. Mol. Cell Biol. 8, 813–824 (2007).

    Article  CAS  PubMed  Google Scholar 

  153. Radisky, D. C. et al. Rac1b and reactive oxygen species mediate MMP-3-induced EMT and genomic instability. Nature 436, 123–127 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Santabarbara-Ruiz, P. et al. ROS-induced JNK and p38 signaling is required for unpaired cytokine activation during Drosophila regeneration. PLOS Genet. 11, e1005595 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  155. Shen, H. M. & Liu, Z. G. JNK signaling pathway is a key modulator in cell death mediated by reactive oxygen and nitrogen species. Free Radic. Biol. Med. 40, 928–939 (2006).

    Article  CAS  PubMed  Google Scholar 

  156. Khan, S. J., Abidi, S. N. F., Skinner, A., Tian, Y. & Smith-Bolton, R. K. The Drosophila Duox maturation factor is a key component of a positive feedback loop that sustains regeneration signaling. PLOS Genet. 13, e1006937 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  157. Pinal, N., Martin, M., Medina, I. & Morata, G. Short-term activation of the Jun N-terminal kinase pathway in apoptosis-deficient cells of Drosophila induces tumorigenesis. Nat. Commun. 9, 1541 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  158. Bianchini, F., Kaaks, R. & Vainio, H. Overweight, obesity, and cancer risk. Lancet Oncol. 3, 565–574 (2002).

    Article  PubMed  Google Scholar 

  159. Font-Burgada, J., Sun, B. & Karin, M. Obesity and cancer: the oil that feeds the flame. Cell Metab. 23, 48–62 (2016).

    Article  CAS  PubMed  Google Scholar 

  160. Altorki, N. K. et al. The lung microenvironment: an important regulator of tumour growth and metastasis. Nat. Rev. Cancer 19, 9–31 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Grzelak, C. A. & Ghajar, C. M. Metastasis 'systems' biology: how are macro-environmental signals transmitted into microenvironmental cues for disseminated tumor cells? Curr. Opin. Cell Biol. 48, 79–86 (2017).

    Article  CAS  PubMed  Google Scholar 

  162. Ishizawar, R. & Parsons, S. J. c-Src and cooperating partners in human cancer. Cancer Cell 6, 209–214 (2004).

    Article  CAS  PubMed  Google Scholar 

  163. Rothwell, P. M. et al. Effect of daily aspirin on risk of cancer metastasis: a study of incident cancers during randomised controlled trials. Lancet 379, 1591–1601 (2012).

    Article  CAS  PubMed  Google Scholar 

  164. Luo, J., Solimini, N. L. & Elledge, S. J. Principles of cancer therapy: oncogene and non-oncogene addiction. Cell 136, 823–837 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Levayer, R. Solid stress, competition for space and cancer: the opposing roles of mechanical cell competition in tumour initiation and growth. Semin. Cancer Biol. https://doi.org/10.1016/j.semcancer.2019.05.004 (2019).

  166. Roncucci, L. & Mariani, F. Prevention of colorectal cancer: how many tools do we have in our basket? Eur. J. Intern. Med. 26, 752–756 (2015).

    Article  PubMed  Google Scholar 

  167. Moya, I. M. et al. Peritumoral activation of the Hippo pathway effectors YAP and TAZ suppresses liver cancer in mice. Science 366, 1029–1034 (2019).

    Article  CAS  PubMed  Google Scholar 

  168. Elisi, G. M. et al. Repurposing of drugs targeting YAP-TEAD functions. Cancers 10, 329 (2018).

    Article  PubMed Central  CAS  Google Scholar 

  169. Oku, Y. et al. Small molecules inhibiting the nuclear localization of YAP/TAZ for chemotherapeutics and chemosensitizers against breast cancers. FEBS Open Bio 5, 542–549 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Rajabi, M. & Mousa, S. A. The role of angiogenesis in cancer treatment. Biomedicines 5, 34 (2017).

    Article  PubMed Central  CAS  Google Scholar 

  171. Wong, P. P., Bodrug, N. & Hodivala-Dilke, K. M. Exploring novel methods for modulating tumor blood vessels in cancer treatment. Curr. Biol. 26, R1161–R1166 (2016).

    Article  CAS  PubMed  Google Scholar 

  172. Wong, P. P. et al. Dual-action combination therapy enhances angiogenesis while reducing tumor growth and spread. Cancer Cell 27, 123–137 (2015).

    Article  CAS  PubMed  Google Scholar 

  173. Pagliarini, R. A. & Xu, T. A genetic screen in Drosophila for metastatic behavior. Science 302, 1227–1231 (2003).

    Article  CAS  PubMed  Google Scholar 

  174. Yamauchi, H. et al. The cell competition-based high-throughput screening identifies small compounds that promote the elimination of RasV12-transformed cells from epithelia. Sci. Rep. 5, 15336 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Madan, E. et al. Flower isoforms promote competitive growth in cancer. Nature 572, 260-264 (2019).

    Article  CAS  PubMed  Google Scholar 

  176. Porazinski, S. et al. EphA2 drives the segregation of ras-transformed epithelial cells from normal neighbors. Curr. Biol. 26, 3220–3229 (2016).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors thank the reviewers for their constructive and thorough reviews that greatly helped to shape the manuscript. The authors thank P. Langton for critical reading and Y. Fujita for constructive criticism of the manuscript. The authors apologize for any studies that they were unable to cite owing to space limitations. Work in the Piddini laboratory is funded by a Wellcome Trust Senior Research Fellowship (grant 205010/Z/16/Z), by a Programme Foundation Award from Cancer Research UK (grant C38607/A26831) and by a start-up fund from the University of Bristol.

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    Medhavi Vishwakarma & Eugenia Piddini

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  1. Medhavi Vishwakarma
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E.P. conceived the ideas for this article and structured the manuscript. E.P. and M.V. wrote the manuscript. E.P. and M.V. conceived the figures. M.V. designed the figures.

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Correspondence to Eugenia Piddini.

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Nature Reviews Cancer thanks T. Igaki, G. Morata and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Vishwakarma, M., Piddini, E. Outcompeting cancer. Nat Rev Cancer 20, 187–198 (2020). https://doi.org/10.1038/s41568-019-0231-8

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