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Cell competition in development, homeostasis and cancer

Abstract

Organ development and homeostasis involve dynamic interactions between individual cells that collectively regulate tissue architecture and function. To ensure the highest tissue fidelity, equally fit cell populations are continuously renewed by stochastic replacement events, while cells perceived as less fit are actively removed by their fitter counterparts. This renewal is mediated by surveillance mechanisms that are collectively known as cell competition. Recent studies have revealed that cell competition has roles in most, if not all, developing and adult tissues. They have also established that cell competition functions both as a tumour-suppressive mechanism and as a tumour-promoting mechanism, thereby critically influencing cancer initiation and development. This Review discusses the latest insights into the mechanisms of cell competition and its different roles during embryonic development, homeostasis and cancer.

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Fig. 1: The types of cell competition.
Fig. 2: General modes of active cell competition.
Fig. 3: Cell competition during embryonic development.
Fig. 4: Cell competition in regulating the architecture and homeostasis of different tissue types.
Fig. 5: Clonal competition in the murine oesophagus.
Fig. 6: Expansion of mutant intestinal stem cells within and beyond the intestinal crypt.
Fig. 7: Cell competition in established cancers.

References

  1. Morata, G. & Ripoll, P. Minutes: mutants of Drosophila autonomously affecting cell division rate. Dev. Biol. https://doi.org/10.1016/0012-1606(75)90330-9 (1975).

    Article  PubMed  Google Scholar 

  2. 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 

  3. Schultz, J. The minute reaction in the development of Drosophila melanogaster. Genetics 14, 366–419 (1929).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Moreno, E. & Basler, K. dMyc transforms cells into super-competitors. Cell https://doi.org/10.1016/S0092-8674(04)00262-4 (2004).

    Article  PubMed  Google Scholar 

  5. de la Cova, C. et al. Drosophila Myc regulates organ size by inducing cell competition. Cell 117, 107–116 (2004).

    PubMed  Google Scholar 

  6. Kim, W. & Jain, R. Picking winners and losers: cell competition in tissue development and homeostasis. Trends Genet. 36, 490–498 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Baker, N. E. Emerging mechanisms of cell competition. Nat. Rev. Genet. 21, 683–697 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Parker, T. M. et al. Cell competition in intratumoral and tumor microenvironment interactions. EMBO J. https://doi.org/10.15252/embj.2020107271 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  9. Vishwakarma, M. & Piddini, E. Outcompeting cancer. Nat. Rev. Cancer 20, 187–198 (2020).

    CAS  PubMed  Google Scholar 

  10. Simons, B. D. & Clevers, H. Strategies for homeostatic stem cell self-renewal in adult tissues. Cell 145, 851–862 (2011).

    CAS  PubMed  Google Scholar 

  11. Vermeulen, L. & Snippert, H. J. Stem cell dynamics in homeostasis and cancer of the intestine. Nat. Rev. Cancer 14, 468–480 (2014).

    CAS  PubMed  Google Scholar 

  12. Klein, A. M. & Simons, B. D. Universal patterns of stem cell fate in cycling adult tissues. Development 138, 3103–3111 (2011).

    CAS  PubMed  Google Scholar 

  13. Clavería, C., Giovinazzo, G., Sierra, R. & Torres, M. Myc-driven endogenous cell competition in the early mammalian embryo. Nature 500, 39–44 (2013). This work provides the first evidence for mammalian supercompetition and demonstrates how stochastic heterogeneity in gene expression can result in temporal fitness differences that drive active elimination.

    PubMed  Google Scholar 

  14. Martincorena, I. et al. Universal patterns of selection in cancer and somatic tissues. Cell 171, 1029–1041.e21 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Wennekamp, S., Mesecke, S., Nédélec, F. & Hiiragi, T. A self-organization framework for symmetry breaking in the mammalian embryo. Nat. Rev. Mol. Cell Biol. 14, 454–461 (2013).

    CAS  Google Scholar 

  16. Kimura, M. The Neutral Theory of Molecular Evolution (Cambridge University Press, 1983).

  17. Ozbudak, E. M., Thattai, M., Kurtser, I., Grossman, A. D. & Van Oudenaarden, A. Regulation of noise in the expression of a single gene. Nat. Genet. 31, 69–73 (2002).

    CAS  PubMed  Google Scholar 

  18. Elowitz, M. B., Levine, A. J., Siggia, E. D. & Swain, P. S. Stochastic gene expression in a single cell. Science 297, 1183–1186 (2002).

    CAS  PubMed  Google Scholar 

  19. De Navascués, J. et al. Drosophila midgut homeostasis involves neutral competition between symmetrically dividing intestinal stem cells. EMBO J. 31, 2473–2485 (2012).

    PubMed  PubMed Central  Google Scholar 

  20. Amoyel, M., Simons, B. D. & Bach, E. A. Neutral competition of stem cells is skewed by proliferative changes downstream of Hh and Hpo. EMBO J. 33, 2295–2313 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Lopez-Garcia, C., Klein, A. M., Simons, B. D. & Winton, D. J. Intestinal stem cell replacement follows a pattern of neutral drift. Science 330, 822–825 (2010).

    CAS  PubMed  Google Scholar 

  22. Snippert, H. J. et al. Intestinal crypt homeostasis results from neutral competition between symmetrically dividing Lgr5 stem cells. Cell 143, 134–144 (2010).

    CAS  PubMed  Google Scholar 

  23. Doupé, D. P. et al. A single progenitor population switches behavior to maintain and repair esophageal epithelium. Science 337, 1091–1093 (2012).

    PubMed  PubMed Central  Google Scholar 

  24. Clayton, E. et al. A single type of progenitor cell maintains normal epidermis. Nature 446, 185–189 (2007).

    CAS  PubMed  Google Scholar 

  25. Scheele, C. L. G. J. et al. Identity and dynamics of mammary stem cells during branching morphogenesis. Nature 542, 313–317 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Bailey, N. T. J. The elements of stochastic processes with applications to the natural sciences (Wiley, 1966).

  27. Williams, M. J., Werner, B., Barnes, C. P., Graham, T. A. & Sottoriva, A. Identification of neutral tumor evolution across cancer types. Nat. Genet. 48, 238–244 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Ritsma, L. et al. Intestinal crypt homeostasis revealed at single-stem-cell level by in vivo live imaging. Nature 507, 362–365 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  30. 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).

    CAS  PubMed  Google Scholar 

  31. Krotenberg Garcia, A. et al. Active elimination of intestinal cells drives oncogenic growth in organoids. Cell Rep. 36, 109307 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 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).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  35. Ellis, S. J. et al. Distinct modes of cell competition shape mammalian tissue morphogenesis. Nature https://doi.org/10.1038/s41586-019-1199-y (2019). This work provides some of the first evidence that the mode of competition within a tissue can change on the basis of an organisms life stage.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Jin, Z. et al. Differentiation-defective stem cells outcompete normal stem cells for niche occupancy in the Drosophila ovary. Cell Stem Cell https://doi.org/10.1016/j.stem.2007.10.021 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  37. van Neerven, S. M. et al. Apc-mutant cells act as supercompetitors in intestinal tumour initiation. Nature 594, 436–441 (2021).

    PubMed  Google Scholar 

  38. Flanagan, D. J. et al. NOTUM from Apc-mutant cells biases clonal competition to initiate cancer. Nature 594, 430–435 (2021).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Ayukawa, S. et al. Epithelial cells remove precancerous cells by cell competition via MHC class I–LILRB3 interaction. Nat. Immunol. 22, 1391–1402 (2021).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Hill, W. et al. EPHA2-dependent outcompetition of KRASG12D mutant cells by wild-type neighbors in the adult pancreas. Curr. Biol. 31, 2550–2560.e5 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  45. 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 

  46. 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 

  47. 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 

  48. Moreno, E., Valon, L., Levillayer, F. & Levayer, R. Competition for space induces cell elimination through compaction-driven ERK downregulation. Curr. Biol. 29, 23–34.e8 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 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 

  50. Alpar, L., Bergantiños, C. & Johnston, L. A. Spatially restricted regulation of Spätzle/Toll signaling during cell competition. Dev. Cell 46, 706 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 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).

    CAS  PubMed  Google Scholar 

  52. 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 

  53. 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 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Frum, T. & Ralston, A. Cell signaling and transcription factors regulating cell fate during formation of the mouse blastocyst. Trends Genet. 31, 402–410 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Saiz, N. & Plusa, B. Early cell fate decisions in the mouse embryo. Reproduction 145, R65–R80 (2013).

    CAS  PubMed  Google Scholar 

  57. Rossant, J. Stem cells and early lineage development. Cell 132, 527–531 (2008).

    CAS  PubMed  Google Scholar 

  58. Ohnishi, Y. et al. Cell-to-cell expression variability followed by signal reinforcement progressively segregates early mouse lineages. Nat. Cell Biol. 16, 27–37 (2014).

    CAS  PubMed  Google Scholar 

  59. Saiz, N., Williams, K. M., Seshan, V. E. & Hadjantonakis, A. K. Asynchronous fate decisions by single cells collectively ensure consistent lineage composition in the mouse blastocyst. Nat. Commun. 7, 1–14 (2016).

    Google Scholar 

  60. Chazaud, C. & Yamanaka, Y. Lineage specification in the mouse preimplantation embryo. Development 143, 1063–1074 (2016).

    CAS  PubMed  Google Scholar 

  61. 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.e5 (2019). This article demonstrates how misspecified cells are recognized and removed from the inner cell mass of the blastocyst during cell fate specification.

    CAS  PubMed  Google Scholar 

  62. Bowling, S. et al. P53 and mTOR signalling determine fitness selection through cell competition during early mouse embryonic development. Nat. Commun. 9, 1–12 (2018).

    Google Scholar 

  63. Takahashi, K. & Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663–676 (2006).

    CAS  PubMed  Google Scholar 

  64. Díaz-Díaz, C. et al. Pluripotency surveillance by Myc-driven competitive elimination of differentiating cells. Dev. Cell 42, 585–599.e4 (2017).

    PubMed  Google Scholar 

  65. 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 

  66. 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 

  67. Montero, S. P., Bowling, S., Pérez-Carrasco, R. & Rodriguez, T. A. Levels of p53 expression determine the competitive ability of embryonic stem cells during the onset of differentiation. bioRxiv https://doi.org/10.1101/2022.02.28.482311 (2022).

    Article  Google Scholar 

  68. Hardarson, T., Hanson, C., Sjögren, A. & Lundin, K. Human embryos with unevenly sized blastomeres have lower pregnancy and implantation rates: indications for aneuploidy and multinucleation. Hum. Reprod. 16, 313–318 (2001).

    CAS  PubMed  Google Scholar 

  69. 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 

  70. Bolton, H. et al. Mouse model of chromosome mosaicism reveals lineage-specific depletion of aneuploid cells and normal developmental potential. Nat. Commun. 7, 1–12 (2016).

    Google Scholar 

  71. Greco, E., Minasi, M. G. & Fiorentino, F. Healthy babies after intrauterine transfer of mosaic aneuploid blastocysts. N. Engl. J. Med. 373, 2089–2090 (2015).

    PubMed  Google Scholar 

  72. Ji, Z., Chuen, J., Kiparaki, M. & Baker, N. Cell competition removes segmental aneuploid cells from drosophila imaginal disc-derived tissues based on ribosomal protein gene dose. Elife 10, e61172 (2021). This study provides a novel mechanism for how aneuploid cells are removed from tissues, based on imbalances of RP gene dosage.

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Marygold, S. J. et al. The ribosomal protein genes and Minute loci of Drosophila melanogaster. Genome Biol. 8, 1–26 (2007).

    Google Scholar 

  74. Baumgartner, M. E., Dinan, M. P., Langton, P. F., Kucinski, I. & Piddini, E. Proteotoxic stress is a driver of the loser status and cell competition. Nat. Cell Biol. 23, 136–146 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Recasens-Alvarez, C. et al. Ribosomopathy-associated mutations cause proteotoxic stress that is alleviated by TOR inhibition. Nat. Cell Biol. 23, 127–135 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Langton, P. F., Baumgartner, M. E., Logeay, R. & Piddini, E. Xrp1 and Irbp18 trigger a feed-forward loop of proteotoxic stress to induce the loser status. PLoS Genet. 17, e1009946 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Ochi, N. et al. Cell competition is driven by Xrp1-mediated phosphorylation of eukaryotic initiation factor 2α. PLoS Genet 17, e1009958 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Uechi, T., Tanaka, T. & Kenmochi, N. A complete map of the human ribosomal protein genes: assignment of 80 genes to the cytogenetic map and implications for human disorders. Genomics 72, 223–230 (2001).

    CAS  PubMed  Google Scholar 

  79. Ajore, R. et al. Deletion of ribosomal protein genes is a common vulnerability in human cancer, especially in concert with TP 53 mutations. EMBO Mol. Med. 9, 498–507 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Lima, A. et al. Cell competition acts as a purifying selection to eliminate cells with mitochondrial defects during early mouse development. Nat. Metab. https://doi.org/10.1101/2020.01.15.900613 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  81. Guiu, J. et al. Tracing the origin of adult intestinal stem cells. Nature 570, 107–111 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Andersen, M. S. et al. Tracing the cellular dynamics of sebaceous gland development in normal and perturbed states. Nat. Cell Biol. 21, 924–932 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. McGinn, J. et al. A biomechanical switch regulates the transition towards homeostasis in oesophageal epithelium. Nat. Cell Biol. 23, 511–525 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 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 

  85. Clevers, H. The intestinal crypt, a prototype stem cell compartment. Cell 154, 274 (2013).

    CAS  PubMed  Google Scholar 

  86. Bartfeld, S. & Koo, B. K. Adult gastric stem cells and their niches. Wiley Interdiscip. Rev. Dev. Biol. https://doi.org/10.1002/wdev.261 (2017).

    Article  PubMed  Google Scholar 

  87. Kozar, S. et al. Continuous clonal labeling reveals small numbers of functional stem cells in intestinal crypts and adenomas. Cell Stem Cell https://doi.org/10.1016/j.stem.2013.08.001 (2013).

    Article  PubMed  Google Scholar 

  88. Han, S. et al. Defining the identity and dynamics of adult gastric isthmus stem cells. Cell Stem Cell 25, 342–356.e7 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Corominas-Murtra, B. et al. Stem cell lineage survival as a noisy competition for niche access. Proc. Natl Acad. Sci. USA 117, 16969–16975 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Huels, D. J. et al. Wnt ligands influence tumour initiation by controlling the number of intestinal stem cells. Nat. Commun. https://doi.org/10.1038/s41467-018-03426-2 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  91. Pentinmikko, N. et al. Notum produced by Paneth cells attenuates regeneration of aged intestinal epithelium. Nature https://doi.org/10.1038/s41586-019-1383-0 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  92. Bruens, L. et al. Calorie restriction increases the number of competing stem cells and decreases mutation retention in the intestine. Cell Rep. https://doi.org/10.1016/j.celrep.2020.107937 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  93. Piedrafita, G. et al. A single-progenitor model as the unifying paradigm of epidermal and esophageal epithelial maintenance in mice. Nat. Commun. 11, 1–15 (2020).

    Google Scholar 

  94. Rompolas, P., Mesa, K. R. & Greco, V. Spatial organization within a niche as a determinant of stem-cell fate. Nature 502, 513–518 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Mesa, K. R. et al. Homeostatic epidermal stem cell self-renewal is driven by local differentiation. Cell Stem Cell 23, 677–686.e4 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Liu, N. et al. Stem cell competition orchestrates skin homeostasis and ageing. Nature https://doi.org/10.1038/s41586-019-1085-7 (2019). This study demonstrates how the epidermal stem cell pool is optimally maintained by physically pushing out less fit stem cells that have decreased adherence to the niche due to reduced COL17A1 levels.

    Article  PubMed  PubMed Central  Google Scholar 

  97. Matsumura, H. et al. Stem cells: hair follicle aging is driven by transepidermal elimination of stem cells via COL17A1 proteolysis. Science 351, aad4395 (2016).

    PubMed  Google Scholar 

  98. Laurenti, E. & Göttgens, B. From haematopoietic stem cells to complex differentiation landscapes. Nature 553, 418–426 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Morrison, S. J. & Scadden, D. T. The bone marrow niche for haematopoietic stem cells. Nature 505, 327–334 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Wilson, A. et al. Hematopoietic stem cells reversibly switch from dormancy to self-renewal during homeostasis and repair. Cell 135, 1118–1129 (2008).

    CAS  PubMed  Google Scholar 

  101. Foudi, A. et al. Analysis of histone 2B-GFP retention reveals slowly cycling hematopoietic stem cells. Nat. Biotechnol. 27, 84–90 (2009).

    CAS  PubMed  Google Scholar 

  102. Haas, S., Trumpp, A. & Milsom, M. D. Causes and consequences of hematopoietic stem cell heterogeneity. Cell Stem Cell 22, 627–638 (2018).

    CAS  PubMed  Google Scholar 

  103. Roch, A. et al. Single-cell analyses identify bioengineered niches for enhanced maintenance of hematopoietic stem cells. Nat. Commun. 8, 1–12 (2017).

    CAS  Google Scholar 

  104. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. 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 

  106. 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 

  107. Baccin, C. et al. Combined single-cell and spatial transcriptomics reveal the molecular, cellular and spatial bone marrow niche organization. Nat. Cell Biol. 22, 38–48 (2019).

    PubMed  PubMed Central  Google Scholar 

  108. Baryawno, N. et al. A cellular taxonomy of the bone marrow stroma in homeostasis and leukemia. Cell 177, 1915–1932.e16 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Tikhonova, A. N. et al. The bone marrow microenvironment at single-cell resolution. Nature 569, 222–228 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Miao, R. et al. Hematopoietic stem cell niches and signals controlling immune cell development and maintenance of immunological memory. Front. Immunol. 11, 600127 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Miao, R., Chun, H., Gomes, A. C., Choi, J. & Pereira, J. P. Competition between hematopoietic stem and progenitor cells controls hematopoietic stem cell compartment size. bioRxiv https://doi.org/10.1101/2021.12.12.472293 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  112. Villa del Campo, C., Clavería, 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 

  113. 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 

  114. Jam, F. A. et al. Neuroepithelial cell competition triggers loss of cellular juvenescence. Sci. Rep. 10, 18044 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. 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 

  116. Kozyrska, K. et al. P53 directs leader cell behavior, migration, and clearance during epithelial repair. Science 375, eabl8876 (2022).

    CAS  PubMed  Google Scholar 

  117. Lee-Six, H. et al. The landscape of somatic mutation in normal colorectal epithelial cells. Nature 574, 532–537 (2019).

    CAS  PubMed  Google Scholar 

  118. Moore, L. et al. The mutational landscape of normal human endometrial epithelium. Nature https://doi.org/10.1038/s41586-020-2214-z (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  119. Martincorena, I. et al. Somatic mutant clones colonize the human esophagus with age. Science https://doi.org/10.1126/science.aau3879 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  120. Akira, Y. et al. Age-related remodelling of oesophageal epithelia by mutated cancer drivers. Nature 565, 312–317 (2019).

    Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Ganuza, M. et al. The global clonal complexity of the murine blood system declines throughout life and after serial transplantation. Blood 133, 1927–1942 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Vogelstein, B. et al. Cancer genome landscapes. Science 340, 1546–1558 (2013).

    Google Scholar 

  124. 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).

    PubMed  Google Scholar 

  125. 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 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Sato, N. et al. The COX-2/PGE2 pathway suppresses apical elimination of RasV12-transformed cells from epithelia. Commun. Biol. 3, 132 (2020).

    PubMed  PubMed Central  Google Scholar 

  128. 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).

    CAS  PubMed  Google Scholar 

  129. Fernandez-Antoran, D. et al. Outcompeting p53-mutant cells in the normal esophagus by redox manipulation. Cell Stem Cell 25, 329–341.e6 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Kajita, M. et al. Filamin acts as a key regulator in epithelial defence against transformed cells. Nat. Commun. 5, 1–13 (2014).

    Google Scholar 

  131. Prior, I. A., Hood, F. E. & Hartley, J. L. The frequency of ras mutations in cancer. Cancer Res. 80, 2669–2974 (2020).

    Google Scholar 

  132. 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 

  133. Pothapragada, S. P., Gupta, P., Mukherjee, S. & Das, T. Matrix mechanics regulates epithelial defence against cancer by tuning dynamic localization of filamin. Nat. Commun. 13, 1–12 (2022).

    Google Scholar 

  134. Greten, F. R. & Grivennikov, S. I. Inflammation and cancer: triggers, mechanisms, and consequences. Immunity 51, 27–41 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Fiore, V. F. et al. Mechanics of a multilayer epithelium instruct tumour architecture and function. Nature 585, 433–439 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. 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 

  137. 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 

  138. Chiba, T. et al. MDCK cells expressing constitutively active Yes-associated protein (YAP) undergo apical extrusion depending on neighboring cell status. Sci. Rep. 6, 1–10 (2016).

    Google Scholar 

  139. Grieve, A. G. & Rabouille, C. Extracellular cleavage of E-cadherin promotes epithelial cell extrusion. J. Cell Sci. 127, 3331–3346 (2014).

    CAS  PubMed  Google Scholar 

  140. Alcolea, M. P. et al. Differentiation imbalance in single oesophageal progenitor cells causes clonal immortalization and field change. Nat. Cell Biol. 16, 612–619 (2014).

    Google Scholar 

  141. Colom, B. et al. Spatial competition shapes the dynamic mutational landscape of normal esophageal epithelium. Nat. Genet. https://doi.org/10.1038/s41588-020-0624-3.

  142. Lowell, S., Jones, P., Le Roux, I., Dunne, J. & Watt, F. M. Stimulation of human epidermal differentiation by Delta-Notch signalling at the boundaries of stem-cell clusters. Curr. Biol. 10, 491–500 (2000).

    CAS  PubMed  Google Scholar 

  143. Zhu, M. et al. Somatic mutations increase hepatic clonal fitness and regeneration in chronic liver disease. Cell 177, 608–621.e12 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Suda, K. et al. Clonal expansion and diversification of cancer-associated mutations in endometriosis and normal endometrium. Cell Rep. 24, 1777–1789 (2018).

    CAS  PubMed  Google Scholar 

  145. Murai, K. et al. Epidermal tissue adapts to restrain progenitors carrying clonal p53 mutations. Cell Stem Cell 23, 687–699.e8 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. Colom, B. et al. Mutant clones in normal epithelium outcompete and eliminate emerging tumours. Nature 598, 510–514 (2021). This article reveals how non-oncogenic mutant clones with a fitness advantage can prevent the expansion of oncogenic clones, thereby reducing the onset of cancer lesions in the murine oesophagus.

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Sandoval, M., Ying, Z. & Beronja, S. Interplay of opposing fate choices stalls oncogenic growth in murine skin epithelium. Elife 10, 1–18 (2021).

    Google Scholar 

  148. Yui, M. A. & Rothenberg, E. V. Developmental gene networks: a triathlon on the course to T cell identity. Nat. Rev. Immunol. 14, 529–545 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Martins, V. C. et al. Thymus-autonomous T cell development in the absence of progenitor import. J. Exp. Med. 209, 1409–1417 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Paiva, R. A. et al. Self-renewal of double-negative 3 early thymocytes enables thymus autonomy but compromises the β-selection checkpoint. Cell Rep. 35, 108967 (2021).

    CAS  PubMed  Google Scholar 

  151. Ballesteros-Arias, L. et al. T cell acute lymphoblastic leukemia as a consequence of thymus autonomy. J. Immunol. 202, 1137–1144 (2019).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  153. Ramos, C. V. et al. Cell competition, the kinetics of thymopoiesis, and thymus cellularity are regulated by double-negative 2 to 3 early thymocytes. Cell Rep. 32, 107910 (2020).

    CAS  PubMed  Google Scholar 

  154. Jaiswal, S. et al. Age-related clonal hematopoiesis associated with adverse outcomes. N. Engl. J. Med. 371, 2488–2498 (2014).

    PubMed  PubMed Central  Google Scholar 

  155. Genovese, G. et al. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N. Engl. J. Med. 371, 2477–2487 (2014).

    PubMed  PubMed Central  Google Scholar 

  156. Watson, C. J. et al. The evolutionary dynamics and fitness landscape of clonal hematopoiesis. Science 367, 1449–1454 (2020).

    CAS  PubMed  Google Scholar 

  157. Shlush, L. I. et al. Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia. Nature 506, 328–333 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  158. Li, Q. et al. Oncogenic Nras has bimodal effects on stem cells that sustainably increase competitiveness. Nature 504, 143–147 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  159. Reuss-Borst, M. A., Bühring, H. J., Klein, G. & Müller, C. A. Adhesion molecules on CD34+ hematopoietic cells in normal human bone marrow and leukemia. Ann. Hematol. 65, 169–174 (1992).

    CAS  PubMed  Google Scholar 

  160. Bajaj, J. et al. CD98-mediated adhesive signaling enables the establishment and propagation of acute myelogenous leukemia. Cancer Cell 30, 792–805 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  161. Saito, Y. et al. Maintenance of the hematopoietic stem cell pool in bone marrow niches by EVI1-regulated GPR56. Leukemia 27, 1637–1649 (2013).

    CAS  PubMed  Google Scholar 

  162. Jan, M. et al. Clonal evolution of preleukemic hematopoietic stem cells precedes human acute myeloid leukemia. Sci. Transl. Med. 4, 149ra118 (2012).

    PubMed  PubMed Central  Google Scholar 

  163. Yum, M. K. et al. Tracing oncogene-driven remodelling of the intestinal stem cell niche. Nature 594, 442–447 (2021). This study elegantly demonstrates how mutant ISCs outcompete normal stem cells by secreting factors that reduce stemness, either directly or via reciprocal signalling with niche cells.

    CAS  PubMed  Google Scholar 

  164. Suijkerbuijk, S. J. E., 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 

  165. Vincent, J. P., Kolahgar, G., Gagliardi, M. & Piddini, E. Steep differences in wingless signaling trigger Myc-independent competitive cell interactions. Dev. Cell https://doi.org/10.1016/j.devcel.2011.06.021 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  166. Boyd, A. L. et al. Acute myeloid leukaemia disrupts endogenous myelo-erythropoiesis by compromising the adipocyte bone marrow niche. Nat. Cell Biol. 19, 1336–1347 (2017).

    CAS  PubMed  Google Scholar 

  167. Boone, P. G. et al. A cancer rainbow mouse for visualizing the functional genomics of oncogenic clonal expansion. Nat. Commun. 10, 5490 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  168. Bruens, L., Ellenbroek, S. I. J., van Rheenen, J. & Snippert, H. J. In vivo imaging reveals existence of crypt fission and fusion in adult mouse intestine. Gastroenterology 153, 674–677.e3 (2017).

    PubMed  Google Scholar 

  169. Nowell, P. C. The clonal evolution of tumor cell populations. Science 194, 23–28 (1976).

    CAS  PubMed  Google Scholar 

  170. Vendramin, R., Litchfield, K. & Swanton, C. Cancer evolution: Darwin and beyond. EMBO J. 40, e108389 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. Black, J. R. M. & McGranahan, N. Genetic and non-genetic clonal diversity in cancer evolution. Nat. Rev. Cancer 21, 379–392 (2021).

    CAS  PubMed  Google Scholar 

  172. Cleary, A. S., Leonard, T. L., Gestl, S. A. & Gunther, E. J. Tumour cell heterogeneity maintained by cooperating subclones in Wnt-driven mammary cancers. Nature https://doi.org/10.1038/nature13187 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  173. Janiszewska, M. et al. Subclonal cooperation drives metastasis by modulating local and systemic immune microenvironments. Nat. Cell Biol. 21, 879–888 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  174. Dong, Y. L. et al. Cooperation between oncogenic Ras and wild-type p53 stimulates STAT non-cell autonomously to promote tumor radioresistance. Commun. Biol. 4, 1–13 (2021).

    Google Scholar 

  175. Calses, P. C., Crawford, J. J., Lill, J. R. & Dey, A. Hippo pathway in cancer: aberrant regulation and therapeutic opportunities. Trends Cancer 5, 297–307 (2019).

    CAS  PubMed  Google Scholar 

  176. Sottoriva, A. et al. Intratumor heterogeneity in human glioblastoma reflects cancer evolutionary dynamics. Proc. Natl Acad. Sci. USA 110, 4009–4014 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  177. Liu, Z. et al. Differential YAP expression in glioma cells induces cell competition and promotes tumorigenesis. J. Cell Sci. 132, jcs225714 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  178. Price, C. J. et al. Genetically variant human pluripotent stem cells selectively eliminate wild-type counterparts through YAP-mediated cell competition. Dev. Cell 56, 2455–2470.e10 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  179. 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 article describes how liver hepatocytes compete with cancer cells and restrain tumour expansion due to relative differences in Hippo pathway signalling. Also see Liu et al. (J. Cell Sci., 2019) for elegant work on how heterogeneity in Hippo signalling between subpopulations of cancer cells results in the active elimination of YAPlow cells by YAPh cells.

    CAS  PubMed  Google Scholar 

  180. Madan, E. et al. Flower isoforms promote competitive growth in cancer. Nature 572, 260–264 (2019). This study reveals the implication of FWE fitness fingerprints in human normal and cancer cells, and demonstrates how cancer cells can utilize these fingerprints to outcompete surrounding stroma and promote tumour expansion.

    CAS  PubMed  Google Scholar 

  181. Petrova, E., López-Gay, J. M., Rhiner, C. & Moreno, E. Flower-deficient mice have reduced susceptibility to skin papilloma formation. DMM Dis. Model. Mech. 5, 553–561 (2012).

    CAS  PubMed  Google Scholar 

  182. Mueller, M. M. & Fusenig, N. E. Friends or foes-bipolar effects of the tumour stroma in cancer. Nat. Rev. Cancer 4, 839–849 (2004).

    CAS  PubMed  Google Scholar 

  183. Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell https://doi.org/10.1016/j.cell.2011.02.013 (2011).

    Article  PubMed  Google Scholar 

  184. Banreti, A. R. & Meier, P. The NMDA receptor regulates competition of epithelial cells in the Drosophila wing. Nat. Commun. 11, 1–14 (2020).

    Google Scholar 

  185. 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 

  186. Chang, C. H. et al. Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell 162, 1229–1241 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  187. 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, 1–13 (2017).

    CAS  Google Scholar 

  188. Madan, E. et al. Cell competition boosts clonal evolution and hypoxic selection in cancer. Trends Cell Biol. 30, 967–978 (2020).

    CAS  PubMed  Google Scholar 

  189. Warburg, O. On the origin of cancer cells. Science 123, 309–314 (1956).

    CAS  PubMed  Google Scholar 

  190. de la Cruz-López, K. G., Castro-Muñoz, L. J., Reyes-Hernández, D. O., García-Carrancá, A. & Manzo-Merino, J. Lactate in the regulation of tumor microenvironment and therapeutic approaches. Front. Oncol. 9, 1143 (2019).

    PubMed  PubMed Central  Google Scholar 

  191. Kedia-Mehta, N. & Finlay, D. K. Competition for nutrients and its role in controlling immune responses. Nat. Commun. 10, 1–8 (2019).

    CAS  Google Scholar 

  192. Cascone, T. et al. Increased tumor glycolysis characterizes immune resistance to adoptive T cell therapy. Cell Metab. 27, 977–987.e4 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  193. Kakiuchi, N. et al. Frequent mutations that converge on the NFKBIZ pathway in ulcerative colitis. Nature 577, 260–265 (2019).

    PubMed  Google Scholar 

  194. Nanki, K. et al. Somatic inflammatory gene mutations in human ulcerative colitis epithelium. Nature 577, 254–259 (2019).

    PubMed  Google Scholar 

  195. Olafsson, S. et al. Somatic evolution in non-neoplastic IBD-affected colon. Cell 182, 672–684.e11 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  196. Zappavigna, S. et al. Anti-inflammatory drugs as anticancer agents. Int. J. Mol. Sci. 21, 2605 (2020).

    CAS  PubMed Central  Google Scholar 

  197. Hsu, J. I. et al. PPM1D mutations drive clonal hematopoiesis in response to cytotoxic chemotherapy. Cell Stem Cell 23, 700–713.e6 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  198. McDermott, D. H. et al. Chromothriptic cure of WHIM syndrome. Cell 160, 686–699 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  199. 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.e8 (2011).

    CAS  PubMed  Google Scholar 

  200. Kobayashi, T. et al. Generation of rat pancreas in mouse by interspecific blastocyst injection of pluripotent stem cells. Cell 142, 787–799 (2010).

    CAS  PubMed  Google Scholar 

  201. Nishimura, T. et al. Generation of functional organs using a cell-competitive niche in intra- and inter-species rodent chimeras. Cell Stem Cell 28, 141–149.e3 (2021).

    CAS  PubMed  Google Scholar 

  202. Zheng, C. et al. Cell competition constitutes a barrier for interspecies chimerism. Nature 592, 272–276 (2021).

    CAS  PubMed  Google Scholar 

  203. Nichols, J., Lima, A. & Rodríguez, T. A. Cell competition and the regulative nature of early mammalian development. Cell Stem Cell 29, 1018–1030 (2022).

    CAS  PubMed  Google Scholar 

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Acknowledgements

S.M.v.N. is supported by ZonMw (Rubicon 452021320) and an EMBO Postdoctoral Fellowship (122-2022, non-stipendiary). This work is supported by Oncode Institute, the New York Stem Cell Foundation and grants from the European Research Council (ERG-CoG 101045612 - NIMICRY) and ZonMw (Vici 09-15018-21-10029) to L.V. L.V. is a New York Stem Cell Foundation–Robertson Stem Cell Investigator. The authors thank the members of the Laboratory for Experimental Oncology and Radiobiology for insightful discussions and comments on a draft of this work.

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Correspondence to Louis Vermeulen.

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L.V. received consultancy fees from Bayer, MSD, Genentech, Servier, and Pierre Fabre, but these had no relation to the content of this publication. S.M.v.N. declares no competing interests.

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Glossary

Fitness

On a cellular level, the relative ability of a cell to remain within a population of cells. On a population level, the relative ability of a clone or genetic variant to remain or expand within a tissue or organism.

Wing disc

A tissue carrying a small number of undifferentiated precursor cells that expand, differentiate and together form the adult wing and most of the notum in Drosophila melanogaster. Wing disc development is a key model to study cell competition.

Hippo signalling

An evolutionarily conserved pathway that controls organ size during development and homeostasis by regulating proliferation, differentiation and cell survival. Hippo signalling is often dysregulated during cancer development, which facilitates tumour expansion.

Epiblast

The pluripotent lineage giving rise to the three germ line layers in a complex process of differentiation and cell fate specification.

Clones

A population of genetically identical cells derived from the same progenitor.

Tissue fixation

When an entire tissue is completely taken over (100%) by the progeny of a single cell or clone, this variant is permanently present in the tissue, also known as monoclonality.

Neutral drift

The spread of genetic variants without a selective advantage.

Terminal end buds

Highly proliferative structures at the end of a duct that drive the development of the mammary gland.

Biased drift

The spread of genetic variants with a selective advantage.

Entosis

A non-apoptotic cell death process in which a cell invades or is engulfed by another cell while still alive.

Live-cell extrusion

A process by which live cells are eliminated from tissues in regions with high cell density (crowding) to maintain optimal cell numbers in the tissue.

Notum

The dorsal portion of the fly thorax.

Scribble

A cell polarity gene that, when gene function is lost, confers a disadvantage on the recipient cell.

Major histocompatibility complex class I

A class of proteins expressed at the cell membrane involved in mediating cellular immunity.

Caspase

A family of proteases that facilitate apoptosis by cleaving cysteines from important cellular structures, thereby disassembling them.

mTOR

Mechanistic target of rapamycin, a kinase that forms a complex (complex 1 or complex 2) with other proteins that together regulate processes such as cell growth, motility and survival.

Crypt fixation

A form of tissue fixation, but in the context of intestinal stem cell dynamics. Crypt fixation occurs when all the cells in a crypt are derived from the progeny of a single intestinal stem cell.

Paneth cells

Secretory epithelial cell type residing in the intestinal crypt bottom, providing important growth factors to support intestinal stem cell function.

Basement membrane

A thin layer of extracellular matrix that supports and signals with the epithelial cells that reside on top of it.

Hemidesmosome

A protein complex that enables stable adherence of epithelial cells to the basement membrane.

Cancer driver genes

A set of genes that when mutated result in a growth advantage that drives tumour formation.

WHIM syndrome

Congenital immune deficiency characterized by warts, hypogammaglobulinaemia, infections and myelokathexis, caused by mutations in the CXCR4 gene.

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van Neerven, S.M., Vermeulen, L. Cell competition in development, homeostasis and cancer. Nat Rev Mol Cell Biol (2022). https://doi.org/10.1038/s41580-022-00538-y

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