Skip to main content

Advertisement

SpringerLink
Log in

Emerging mechanisms of cell competition

  • Review Article
  • Published:

From Nature Reviews Genetics

View current issue Sign up to alerts

An Author Correction to this article was published on 28 August 2020

This article has been updated

Abstract

The growth and survival of cells within tissues can be affected by ‘cell competition’ between different cell clones. This phenomenon was initially recognized between wild-type cells and cells with mutations in ribosomal protein (Rp) genes in Drosophila melanogaster. However, competition also affects D. melanogaster cells with mutations in epithelial polarity genes, and wild-type cells exposed to ‘super-competitor’ cells with mutation in the Salvador–Warts–Hippo tumour suppressor pathway or expressing elevated levels of Myc. More recently, cell competition and super-competition were recognized in mammalian development, organ homeostasis and cancer. Genetic and cell biological studies have revealed that mechanisms underlying cell competition include the molecular recognition of ‘different’ cells, signalling imbalances between distinct cell populations and the mechanical consequences of differential growth rates; these mechanisms may also involve innate immune proteins, p53 and changes in translation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1: The basics of cell competition.
Fig. 2: Examples of cell competition.
Fig. 3: Cell competition of Rp+/– cells in mammals.
Fig. 4: Interactions between cell populations leading to cell competition.
Fig. 5: Mechanisms of cell competition.
Fig. 6: Current mechanistic understanding of epithelial defence against cancer.

Similar content being viewed by others

Change history

References

  1. Buss, R. R., Sun, W. & Oppenheim, R. W. Adaptive roles of programmed cell death during nervous system development. Annu. Rev. Neurosci. 29, 1–35 (2006).

    CAS  PubMed  Google Scholar 

  2. Morata, G. & Ripoll, P. Minutes: mutants of Drosophila autonomously affecting cell division rate. Dev. Biol. 42, 211–221 (1975). This paper recognizes the specific loss of Rp heterozygous mutant cells from certain growing tissues in D. melanogaster only in the presence of wild-type cells, initiating the study of cell competition.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  6. Kale, A., Li, W., Lee, C. H. & Baker, N. E. Apoptotic mechanisms during competition of ribosomal protein mutant cells: roles of the initiator caspases Dronc and Dream/Strica. Cell Death Differ. 22, 1300–1312 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. de la Cova, C., Abril, M., Bellosta, P., Gallant, P. & Johnston, L. Drosophila myc regulates organ size by inducing cell competition. Cell 117, 107–116 (2004). Together with Moreno and Basler (2004), this paper reports that normal cells were specifically lost through competitive interactions with nearby cells expressing elevated Myc levels.This paper also shows how cell competition can compensate for certain developmental growth disparities.

    PubMed  Google Scholar 

  8. Moreno, E. & Basler, K. dMyc transforms cells into super-competitors. Cell 117, 117–129 (2004). Together with de la Cova et al. (2004), this paper reports that normal cells were specifically lost through competitive interactions with nearby cells expressing elevated Myc levels.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Claveria, C., Giovinazzo, G., Sierra, R. & Torres, M. Myc-driven endogenous cell competition in the early mammalian embryo. Nature 500, 39–44 (2013).This paper uses elegant transgenic approaches to show that cells in normal mouse blastocyst are eliminated by apoptosis when competing with cells expressing modestly elevated Myc levels, and suggests that cell competition also occurs in normal mouse embryogenesis.

    CAS  PubMed  Google Scholar 

  14. Ellis, S. J. et al. Distinct modes of cell competition shape mammalian tissue morphogenesis. Nature 569, 497–502 (2019). This paper presents a detailed analysis of the consequences of reduced Mycn function for cell competition in the embryonic mouse epidermis and its functional consequences.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Oertel, M., Menthena, A., Dabeva, M. D. & Shafritz, D. A. Cell competition leads to a high level of normal liver reconstitution by transplanted fetal liver stem/progenitor cells. Gastroenterology 130, 507–520 (2006).

    PubMed  Google Scholar 

  16. Ding, J. et al. Spontaneous hepatic repopulation in transgenic mice expressing mutant human α1-antitrypsin by wild-type donor hepatocytes. J. Clin. Invest. 121, 1930–1934 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Menthena, A. et al. Activin A, p15INK4b signaling, and cell competition promote stem/progenitor cell repopulation of livers in aging rats. Gastroenterology 140, 1009–1020 (2011).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  21. Paiva, R. A., Ramos, C. V. & Martins, V. C. Thymus autonomy as a prelude to leukemia. FEBS J. 285, 4565–4574 (2018).

    CAS  PubMed  Google Scholar 

  22. 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).

    CAS  PubMed  Google Scholar 

  23. Tarkowski, A. K., Witkowska, A. & Opas, J. Development of cytochalasin in B-induced tetraploid and diploid/tetraploid mosaic mouse embryos. J. Embryol. Exp. Morphol. 41, 47–64 (1977).

    CAS  PubMed  Google Scholar 

  24. Nagy, A. et al. Embryonic stem cells alone are able to support fetal development in the mouse. Development 110, 815–821 (1990).

    CAS  PubMed  Google Scholar 

  25. Horii, T. et al. p53 suppresses tetraploid development in mice. Sci. Rep. 5, 8907 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Diaz-Diaz, C. et al. Pluripotency surveillance by myc-driven competitive elimination of differentiating cells. Dev. Cell 42, 585–599 (2017). This paper describes how competition based on Myc expression levels helps maintain a pluripotent mouse epiblast (see Zhang (2017) for the role of TEAD-YAP).

    CAS  PubMed  Google Scholar 

  30. Hashimoto, M. & Sasaki, H. Epiblast formation by TEAD-YAP-dependent expression of pluripotency factors and competitive elimination of unspecified cells. Dev. Cell 50, 139–154 (2019). This paper describes how diminishing Hippo signalling and elevated TEAD-YAP activity are required for pluripotency in the early mouse embryo and that competition between cells with differing TEAD1 activities helps define a pluripotent epiblast (see Bowling et al. (2018) for similar studies of Myc).

    CAS  PubMed  Google Scholar 

  31. 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).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  33. 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).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

  38. Yamauchi, H. & Fujita, Y. Epithelial self-defense against cancer. Cell Res. 22, 1527–1529 (2012).

    PubMed  PubMed Central  Google Scholar 

  39. 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).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  41. van Echten-Arends, J. et al. Chromosomal mosaicism in human preimplantation embryos: a systematic review. Hum. Reprod. Update 17, 620–627 (2011).

    PubMed  Google Scholar 

  42. McCoy, R. C. Mosaicism in preimplantation human embryos: when chromosomal abnormalities are the norm. Trends Genet. 33, 448–463 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Zamani Esteki, M. et al. In vitro fertilization does not increase the incidence of de novo copy number alterations in fetal and placental lineages. Nat. Med. 25, 1699–1705 (2019).

    CAS  PubMed  Google Scholar 

  44. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Andriani, G. A. et al. Whole chromosome aneuploidy in the brain of Bub1bH/H and Ercc1–/Δ7 mice. Hum. Mol. Genet. 25, 755–765 (2016).

    CAS  PubMed  Google Scholar 

  46. Martincorena, I. & Campbell, P. J. Somatic mutation in cancer and normal cells. Science 349, 1483–1489 (2015).

    CAS  PubMed  Google Scholar 

  47. Steensma, D. P. et al. Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes. Blood 126, 9–16 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Martincorena, I. et al. Somatic mutant clones colonize the human esophagus with age. Science 362, 911–917 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Yizhak, K. et al. RNA sequence analysis reveals macroscopic somatic clonal expansion across normal tissues. Science 364, eaaw0726 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. de la Cova, C. et al. Supercompetitor status of Drosophila Myc cells requires p53 as a fitness sensor to reprogram metabolism and promote viability. Cell Metab. 19, 470–483 (2014).

    PubMed  PubMed Central  Google Scholar 

  52. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Senoo-Matsuda, N. & Johnston, L. A. Soluble factors mediate competitive and cooperative interactions between cells expressing different levels of Drosophila Myc. Proc. Natl Acad. Sci. USA 104, 18543–18548 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Nagata, R., Nakamura, M., Sanaki, Y. & Igaki, T. Cell competition is driven by autophagy. Dev. Cell 51, 99–112 (2019).

    CAS  PubMed  Google Scholar 

  56. Fernandez-Antoran, D. et al. Outcompeting p53-mutant cells in the normal esophagus by redox manipulation. Cell Stem Cell 25, 329–341 (2019). This paper describes how low-level ionizing radiation and antioxidants determine the contribution of Tp53 mutated cells to the mouse oesophagus through cell competition.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Banreti, A. R. & Meier, P. The NMDA receptor regulates competition of epithelial cells in the Drosophila wing. Nat. Commun. 11, 2228 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Tanimura, N. & Fujita, Y. Epithelial defense against cancer (EDAC). Semin. Cancer Biol 63, 44–48 (2019). This paper presents a recent review of the competitive elimination of cells with oncogenic genotypes from co-cultures with wild-type MDCK cells during EDAC.

    PubMed  Google Scholar 

  59. Martin, F. A., Herrera, S. C. & Morata, G. Cell competition, growth and size control in the Drosophila wing imaginal disc. Development 136, 3747–3756 (2009).

    CAS  PubMed  Google Scholar 

  60. 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).

    CAS  PubMed  Google Scholar 

  61. Draptchinskaia, N. et al. The gene encoding ribosomal protein S19 is mutated in Diamond–Blackfan anaemia. Nat. Genet. 21, 169–175 (1999).

    CAS  PubMed  Google Scholar 

  62. Ulirsch, J. C. et al. The genetic landscape of Diamond–Blackfan anemia. Am. J. Hum. Genet. 103, 930–947 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Garelli, E. et al. Spontaneous remission in a Diamond–Blackfan anaemia patient due to a revertant uniparental disomy ablating a de novo RPS19 mutation. Br. J. Haematol. 185, 994–998 (2019).

    PubMed  Google Scholar 

  64. Jongmans, M. C. J. et al. Somatic reversion events point towards RPL4 as a novel disease gene in a condition resembling Diamond–Blackfan anemia. Haematologica 103, e607–e609 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Venugopal, P. et al. Self-reverting mutations partially correct the blood phenotype in a Diamond Blackfan anemia patient. Haematologica 102, e506–e509 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Deisenroth, C., Franklin, D. A. & Zhang, Y. The evolution of the ribosomal protein–MDM2–p53 pathway. Cold Spring Harb. Perspect. Med. https://doi.org/10.1101/cshperspect.a026138 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  67. Danilova, N. & Gazda, H. T. Ribosomopathies: how a common root can cause a tree of pathologies. Dis. Model. Mech. 8, 1013–1026 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Matamoro-Vidal, A. & Levayer, R. Multiple influences of mechanical forces on cell competition. Curr. Biol. 29, R762–R774 (2019). This paper presents a recent review of mechanical forces in cell competition.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  71. 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). This paper identifies a receptor–ligand interaction at the interface between scrib mutant cells and wild-type cells in D. melanogaster that results in the recognition and elimination of the scrib mutant cells.

    CAS  PubMed  Google Scholar 

  72. Vaughen, J. & Igaki, T. Slit–Robo repulsive signaling extrudes tumorigenic cells from epithelia. Dev. Cell 39, 683–695 (2016). This paper describes the contribution of Slit–Robo signalling, better known for its function in neuronal morphogenesis, to the elimination of D. melanogaster imaginal disc cells mutated for scrib.

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  74. Sanaki, Y., Nagata, R., Kizawa, D., Leopold, P. & Igaki, T. Hyperinsulinemia drives epithelial tumorigenesis by abrogating cell competition. Dev. Cell 53, 379–389, https://doi.org/10.1016/j.devcel.2020.04.008 (2020).

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Alpar, L., Bergantinos, C. & Johnston, L. A. Spatially restricted regulation of Spätzle/Toll signaling during cell competition. Dev. Cell 46, 706–719 (2018). This paper suggests how wild-type cells in D. melanogaster can be eliminated by competition with cells expressing more Myc without the need for any direct molecular recognition of the differences between cells.

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 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 https://doi.org/10.7554/eLife.39939 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  78. Mao, Y. et al. Differential proliferation rates generate patterns of mechanical tension that orient tissue growth. EMBO J. 32, 2790–2803 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Aegerter-Wilmsen, T. et al. Exploring the effects of mechanical feedback on epithelial topology. Development 137, 499–506 (2010).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  84. Li, W., Kale, A. & Baker, N. E. Oriented cell division as a response to cell death and cell competition. Curr. Biol. 19, 1821–1826 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Levayer, R., Hauert, B. & Moreno, E. Cell mixing induced by myc is required for competitive tissue invasion and destruction. Nature 524, 476–480 (2015).

    CAS  PubMed  Google Scholar 

  86. Wigglesworth, V. B. Wound healing in an insect (Rhodnius prolixus Hemiptera). J. Exp. Biol. 14, 364–381 (1937).

    CAS  Google Scholar 

  87. Puliafito, A. et al. Collective and single cell behavior in epithelial contact inhibition. Proc. Natl Acad. Sci. USA 109, 739–744 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Gudipaty, S. A. et al. Mechanical stretch triggers rapid epithelial cell division through Piezo1. Nature 543, 118–121 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Wagstaff, L. et al. Mechanical cell competition kills cells via induction of lethal p53 levels. Nat. Commun. 7, 11373 (2016). This paper explains how the mechanical effects of SCRIB knockdown on MDCK cells in culture lead to their elimination when co-cultured with wild-type MDCK cells, and also provides an example of where differences in p53 activity between cells contribute to cell competition.

    CAS  PubMed  PubMed Central  Google Scholar 

  91. 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).

    PubMed  PubMed Central  Google Scholar 

  92. Kale, A. et al. Ribosomal protein S12e has a distinct function in cell competition. Dev. Cell 44, 42–55 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Lee, C. H. et al. A regulatory response to ribosomal protein mutations controls translation, growth, and cell competition. Dev. Cell 46, 456–469 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Heijnen, H. F. et al. Ribosomal protein mutations induce autophagy through S6 kinase inhibition of the insulin pathway. PLoS Genet. 10, e1004371 (2014).

    PubMed  PubMed Central  Google Scholar 

  95. Baillon, L., Germani, F., Rockel, C., Hilchenbach, J. & Basler, K. Xrp1 is a transcription factor required for cell competition-driven elimination of loser cells. Sci. Rep. 8, 17712 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Ji, Z. et al. Drosophila RpS12 controls translation, growth, and cell competition through Xrp1. PLoS Genet. 15, e1008513 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Donati, G., Peddigari, S., Mercer, C. A. & Thomas, G. 5S ribosomal RNA is an essential component of a nascent ribosomal precursor complex that regulates the Hdm2–p53 checkpoint. Cell Rep. 4, 87–98 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Deisenroth, C. & Zhang, Y. Ribosome biogenesis surveillance: probing the ribosomal protein–Mdm2–p53 pathway. Oncogene 29, 4253–4260 (2010).

    CAS  PubMed  Google Scholar 

  99. Baker, N. E., Kiparaki, M. & Khan, C. A potential link between p53, cell competition and ribosomopathy in mammals and in Drosophila. Dev. Biol. 446, 17–19 (2019). This paper presents a recent review of cell competition mechanisms involving p53 and related genes.

    CAS  PubMed  Google Scholar 

  100. 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).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  102. 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 

  103. 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).

    CAS  PubMed  Google Scholar 

  104. Merino, M. M. et al. Elimination of unfit cells maintains tissue health and prolongs lifespan. Cell 160, 461–476 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Madan, E. et al. Flower isoforms promote competitive growth in cancer. Nature 572, 260–264 (2019). This paper describes the contributions of hFWE proteins, encoding potential calcium channels, to the development of cancer in humans and in mouse models.

    CAS  PubMed  Google Scholar 

  106. Xu, T. & Rubin, G. M. The effort to make mosaic analysis a household tool. Development 139, 4501–4503 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Lewandoski, M. Conditional control of gene expression in the mouse. Nat. Rev. Genet. 2, 743–755 (2001).

    CAS  PubMed  Google Scholar 

  108. Kwan, K. M. Conditional alleles in mice: practical considerations for tissue-specific knockouts. Genesis 32, 49–62 (2002).

    CAS  PubMed  Google Scholar 

  109. Merino, M. M., Levayer, R. & Moreno, E. Survival of the fittest: essential roles of cell competition in development, aging, and cancer. Trends Cell Biol. 26, 776–788 (2016).

    PubMed  Google Scholar 

  110. Lee, C. H., Rimesso, G., Reynolds, D. M., Cai, J. & Baker, N. E. Whole-genome sequencing and iPLEX MassARRAY genotyping map an EMS-induced mutation affecting cell competition in Drosophila melanogaster. G3 6, 3207–3217 (2016).

    PubMed  PubMed Central  Google Scholar 

  111. Bellen, H. J. et al. The Drosophila Gene Disruption Project: progress using transposons with distinctive site specificities. Genetics 188, 731–743 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Thibault, S. T. et al. A complementary transposon tool kit for Drosophila melanogaster using P and piggyBac. Nat. Genet. 36, 283–287 (2004).

    CAS  PubMed  Google Scholar 

  113. Parks, A. L. et al. Systematic generation of high-resolution deletion coverage of the Drosophila melanogaster genome. Nat. Genet. 36, 288–292 (2004).

    CAS  PubMed  Google Scholar 

  114. Ryder, E. et al. The DrosDel deletion collection: a Drosophila genomewide chromosomal deficiency resource. Genetics 177, 615–629 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Dietzl, G. et al. A genome-wide transgenic RNAi library for conditional gene inactivation in Drosophila. Nature 448, 151–156 (2007).

    CAS  PubMed  Google Scholar 

  116. Hu, Y. et al. FlyRNAi.org — the database of the Drosophila RNAi Screening Center and Transgenic RNAi Project: 2017 update. Nucleic Acids Res. 45, D672–D678 (2017).

    CAS  PubMed  Google Scholar 

  117. Yamamoto, M. T. Drosophila genetic resource and stock center; the National BioResource Project. Exp. Anim. 59, 125–138 (2010).

    CAS  PubMed  Google Scholar 

  118. Cook, K. R., Parks, A. L., Jacobus, L. M., Kaufman, T. C. & Matthews, K. A. New research resources at the Bloomington Drosophila Stock Center. Fly 4, 88–91 (2010).

    CAS  PubMed  Google Scholar 

  119. 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).

    CAS  PubMed  Google Scholar 

  120. Kaiser, A. M. & Attardi, L. D. Deconstructing networks of p53-mediated tumor suppression in vivo. Cell Death Differ. 25, 93–103 (2018).

    CAS  PubMed  Google Scholar 

  121. Christophorou, M. A. et al. Temporal dissection of p53 function in vitro and in vivo. Nat. Genet. 37, 718–726 (2005).

    CAS  PubMed  Google Scholar 

  122. Christophorou, M. A., Ringshausen, I., Finch, A. J., Swigart, L. B. & Evan, G. I. The pathological response to DNA damage does not contribute to p53-mediated tumour suppression. Nature 443, 214–217 (2006).

    CAS  PubMed  Google Scholar 

  123. Hinkal, G., Parikh, N. & Donehower, L. A. Timed somatic deletion of p53 in mice reveals age-associated differences in tumor progression. PLoS ONE 4, e6654 (2009).

    PubMed  PubMed Central  Google Scholar 

  124. Jiang, D. et al. Full p53 transcriptional activation potential is dispensable for tumor suppression in diverse lineages. Proc. Natl Acad. Sci. USA 108, 17123–17128 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Brady, C. A. et al. Distinct p53 transcriptional programs dictate acute DNA-damage responses and tumor suppression. Cell 145, 571–583 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Li, T. et al. Loss of p53-mediated cell-cycle arrest, senescence and apoptosis promotes genomic instability and premature aging. Oncotarget 7, 11838–11849 (2016).

    PubMed  PubMed Central  Google Scholar 

  127. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Thompson, B. J. et al. Tumor suppressor properties of the ESCRT-II complex component Vps25 in Drosophila. Dev. Cell 9, 711–720 (2005).

    CAS  PubMed  Google Scholar 

  129. Moberg, K. H., Schelble, S., Burdick, S. K. & Hariharan, I. K. Mutations in erupted, the Drosophila ortholog of mammalian tumor susceptibility gene 101, elicit non-cell-autonomous overgrowth. Dev. Cell 9, 699–710 (2005).

    CAS  PubMed  Google Scholar 

  130. 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 (2014).

    CAS  PubMed  Google Scholar 

  131. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Fu, W. et al. Squamous cell carcinoma-related oncogene (SCCRO) family members regulate cell growth and proliferation through their cooperative and antagonistic effects on cullin neddylation. J. Biol. Chem. 291, 6200–6217 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Casas-Tinto, S., Maraver, A., Serrano, M. & Ferrus, A. Troponin-I enhances and is required for oncogenic overgrowth. Oncotarget 7, 52631–52642 (2016).

    PubMed  PubMed Central  Google Scholar 

  134. Metzstein, M. M. & Krasnow, M. A. Functions of the nonsense-mediated mRNA decay pathway in Drosophila development. PLoS Genet. 2, e180 (2006).

    PubMed  PubMed Central  Google Scholar 

  135. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Hafezi, Y., Bosch, J. A. & Hariharan, I. K. Differences in levels of the transmembrane protein Crumbs can influence cell survival at clonal boundaries. Dev. Biol. 368, 358–369 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  139. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Yao, C. K. et al. A synaptic vesicle-associated Ca2+ channel promotes endocytosis and couples exocytosis to endocytosis. Cell 138, 947–960 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. 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). This paper describes how tumour cells and surrounding normal cells compete through the expression of Hippo pathway effectors to respectively promote or restrict tumour expansion in a mouse model of liver cancer.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The author thanks H. Buelow, S. Emmons, C. Khan, M. Kiparaki and the reviewers for comments on the manuscript and C.-H. Lee for Figure 1b. Research into cell competition mechanisms in the author’s laboratory is supported by NIH grants GM104213 and GM120451 and the Albert Einstein College Human Genetics Program.

Author information

Authors and Affiliations

  1. Department of Genetics, Department of Developmental and Molecular Biology, Department of Ophthalmology and Visual Sciences, Albert Einstein College of Medicine, New York, NY, USA

    Nicholas E. Baker

Authors
  1. Nicholas E. Baker
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nicholas E. Baker.

Ethics declarations

Competing interests

The author declares no competing interests.

Additional information

Peer review information

Nature Reviews Genetics thanks T. Igaki, L. Johnston, J.-P. Vincent and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

Extrusion

The progressive ejection of a single cell from an epithelium. Extrusion usually maintains the epithelial barrier as surrounding cells close in and eventually contact one another to maintain a seal.

Aneuploid cells

Cells with abnormal chromosome complements due to missing or additional copies of individual chromosomes. Aneuploid cells are found in most cancers and are a cause of birth defects and miscarriage.

Spindle assembly checkpoint

A process that can arrest the cell cycle to ensure proper coupling of chromosomes to the mitotic spindle, without which chromosome segregation errors often result.

Diamond–Blackfan anaemia

A dominant Mendelian disease often characterized by childhood anaemia caused in the majority of cases by heterozygous mutations or deletions affecting 1 of more than 20 ribosomal protein genes.

Apical–basal axis

The distinction in epithelial cells between the apical surface that faces the exterior or lumen and the basal surface that faces the interior.

Adhesion junctions

The junctions where epithelial cells bind one another through cadherin adhesion molecules expressed on each cell surface.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Baker, N.E. Emerging mechanisms of cell competition. Nat Rev Genet 21, 683–697 (2020). https://doi.org/10.1038/s41576-020-0262-8

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41576-020-0262-8

  • Springer Nature Limited

This article is cited by

Search

Navigation