Cell Competition

Abstract

Cell competition is a conserved mechanism by which unfit cells are outcompeted by fitter neighbours. This quality control mechanism allows the maintenance and propagation of fitter cells, by potentiating the elimination of unfit cells from tissues. Cell competition plays a central role during embryogenesis and in adulthood, contributing to proper development and preservation of tissues homeostasis. The absence of fitness control impacts organ function, which ultimately results in shorten lifespan and disease development. In fact, impairment of cell competition or the appropriation of this process by pre‐malignant cells can allow the expansion of potentially dangerous cells leading to tumorigenesis. Different molecular mechanisms and strategies have been described to be required for the elimination of unfit cells depending on the tissue context and genetics.

Key Concepts

  • Cell competition actively takes place since embryonic stages, throughout development and in the adult.
  • Cell competition is a conserved mechanism in multicellular animals.
  • When in the presence of fitter cells, unfit cells are eliminated from tissues by cell competition.
  • The context and genes involved determine the mechanism by which loser cells are eliminated.
  • Selection of fit cells to be maintained in tissues promote homeostasis and improves lifespan.
  • Accumulation of viable but less fit cells is detrimental for the organism.
  • Pre‐malignant cells may hijack the cell competition mechanism, leading to tumour initiation.

Keywords: Cell competition; supercompetition; cell fitness; homeostasis; development; cancer

Figure 1. Distinct modes of cell competition based on cell–cell contact requirement (direct or indirect) and the genotype of winner and loser cells. (a) Polarity deficient cells such as scrib mutant cells are eliminated through direct cell–cell contact. Wild‐type winner cells restrict EGFR signalling pathway in mutated cells promoting their elimination in a JNK‐dependent manner, via trans‐interaction of Sas‐PTP10D. (b) Supercompetitor Myc cells eliminate wild‐type cells trough cell intercalation. Myc‐driven cell mixing increases the surface of contact between winner and loser cells, promoting the elimination of the later through direct cell fitness comparison in a Flower (Fwe)‐dependent manner. Loser cells express the Fwe lose isoform which leads to the activation of the fitness sensor, azot, inducing hid‐dependent apoptosis. The secreted protein Sparc is expressed by these cells to provide protection to those that are only transiently unfit. (c) Reduction of survival factor/receptor levels and impairment of signalling transduction turns cells into losers. Downregulation of Dpp signalling pathway allows the transcriptional activation of brinker (brk), resulting in JNK‐dependent apoptosis. (d) The mutationally activated form of Ras oncogene (RasV12) fosters clonal expansion by compressing the neighbour wild‐type cells. These cells with less resistance to mechanical stress downregulate EGFR/ERK signalling pathway, allowing the expression of the pro‐apoptotic gene, hid. Note that in indirect cell competition (c and d) the elimination of less fit cells does not require direct contact with winners.
Figure 2. Impact of injury‐induced cell competition in adult homeostasis. (a) The injury of Drosophila adult brain induces proliferation and differentiation of quiescent adult neural progenitor cells, originating new neurons. Upon direct fitness comparison with neighbour fitter neurons, unfit neurons are eliminated by apoptosis. (b) Maintenance of epidermal stem cells (SC) with higher levels of COL17A1 (COL17A1high) via symmetric cell division (SCD) of these winner SC and asymmetric cell division (ACD) of COL17A1 low levels (COL17A1low) loser SC guarantees the homeostasis of the skin. Upon skin excision, ACD of fitter SC ensures wound healing efficiency.
Figure 3. The effect of external factors on cell competition. (a) In the intestinal and pancreatic epithelia, RasV12‐transformed cells are identified as losers by the wild‐type cells and eliminated apically. This mechanism called Epithelial Defence Against Cancer is blocked when mice are kept on high‐fat diet, potentiating the development of tumours. (b) In the hematopoietic system, differences in p53 levels trigger cell competition upon irradiation, where p53‐deficient cells outcompete wild‐type cells that acquire senescence‐like state. Homeostatic stress does not induce cell competition based on p53 levels.
close

References

Akagi K, Kenneth AW, Katewa SD, et al. (2018) Dietary restriction improves intestinal cellular fitness to enhance gut barrier function and lifespan in D. melanogaster. PLoS Genetics 14 (11): e1007777. DOI: 10.1073/pnas.1900055116.

Akieda Y, Ogamino S, Furuie H, et al. (2019) Cell competition corrects noisy Wnt morphogen gradients to achieve robust patterning in the zebrafish embryo. Nature Communications 10 (1): 1–17. DOI: 10.1038/s41467‐019‐12609‐4.

Baillon L, Germani F, Rockel C, Hilchenbach J and Basler K (2018) Xrp1 is a transcription factor required for cell competition‐driven elimination of loser cells. Scientific Reports 8 (1): 1–10. DOI: 10.1038/s41598‐018‐36277‐4.

Bondar T and Medzhitov R (2010) p53‐Mediated hematopoietic stem and progenitor cell competition. Cell Stem Cell 6 (4): 309–322. DOI: 10.1016/j.stem.2010.03.002.

Bowling S, Di Gregorio A, Sancho M, et al. (2018) P53 and mTOR signalling determine fitness selection through cell competition during early mouse embryonic development. Nature Communications 9 (1). DOI: 10.1038/s41467‐018‐04167‐y.

Brás‐Pereira C and Moreno E (2018) Mechanical cell competition. Current Opinion in Cell Biology 51: 15–21. DOI: 10.1016/j.ceb.2017.10.003.

Burke R and Basler K (1996) Dpp receptors are autonomously required for cell proliferation in the entire developing Drosophila wing. Development 122 (7): 2261–2269. DOI: 10.5167/uzh‐998.

Chen CL, Schroeder MC, Kango‐Singh M, Tao C and Halder G (2012) Tumor suppression by cell competition through regulation of the Hippo pathway. Proceedings of the National Academy of Sciences of the United States of America 109 (2): 484–489. DOI: 10.1073/pnas.1113882109.

Clavería C, Giovinazzo G, Sierra R and Torres M (2013) Myc‐driven endogenous cell competition in the early mammalian embryo. Nature 500 (7460): 39–44. DOI: 10.1038/nature12389.

Coelho DS, Schwartz S, Merino MM, et al. (2018) Culling less fit neurons protects against amyloid‐β‐induced brain damage and cognitive and motor decline. Cell Reports 25 (13): 3661–3673.e3. DOI: 10.1016/j.celrep.2018.11.098.

De la Cova C, Senoo‐Matsuda N, Ziosi M, et al. (2014) Supercompetitor status of Drosophila Myc cells requires p53 as a fitness sensor to reprogram metabolism and promote viability. Cell Metabolism 19 (3): 470–483. DOI: 10.1016/j.cmet.2014.01.012.

Di Gregorio A, Bowling S and Rodriguez TA (2016) Cell competition and its role in the regulation of cell fitness from development to cancer. Developmental Cell 38 (6): 621–634. DOI: 10.1016/j.devcel.2016.08.012.

Eisenhoffer GT, Loftus PD, Yoshigi M, et al. (2012) Crowding induces live cell extrusion to maintain homeostatic cell numbers in epithelia. Nature 484 (7395): 546–549. DOI: 10.1038/nature10999.

Fahey‐Lozano N, La Marca JE, Portela M and Richardson HE (2019) The Drosophila model in cancer – 3. Drosophila models of cell polarity and cell competition in tumourigenesis. In: Deng W‐M (ed.) Advances in Experimental Medicine and Biology, vol. 1167. DOI: 10.1007/978‐3‐030‐23629‐8.

Fernandez‐Antoran D, Piedrafita G, Murai K, et al. (2019) Outcompeting p53‐mutant cells in the normal esophagus by redox manipulation. Cell Stem Cell 25 (3): 329–341.e6. DOI: 10.1016/j.stem.2019.06.011.

Ferraiuolo M, Verduci L, Blandino G and Strano S (2017) Mutant p53 protein and the Hippo transducers YAP and TAZ: a critical oncogenic node in human cancers. International Journal of Molecular Sciences 18 (5): 961. DOI: 10.3390/ijms18050961.

Igaki T, Pastor‐Pareja JC, Aonuma H, Miura M and Xu T (2009) Intrinsic tumor suppression and epithelial maintenance by endocytic activation of eiger/TNF signaling in Drosophila. Developmental Cell 16 (3): 458–465. DOI: 10.1016/j.devcel.2009.01.002.

Ji Z, Kiparaki M, Folgado V, et al. (2019) Drosophila RpS12 controls translation, growth, and cell competition through Xrp1. PLoS Genetics 15 (12): 1–25. DOI: 10.1371/journal.pgen.1008513.

Kajita M and Fujita Y (2015) EDAC: Epithelial defence against cancer – cell competition between normal and transformed epithelial cells in mammals. Journal of Biochemistry 158 (1): 15–23. DOI: 10.1093/jb/mvv050.

Kale A, Ji Z, Kiparaki M, et al. (2018) Ribosomal protein S12e has a distinct function in cell competition. Developmental Cell 44 (1): 42–55.e4. DOI: 10.1016/j.devcel.2017.12.007.

Katsukawa M, Ohsawa S, Zhang L, Yan Y and Igaki T (2018) Serpin facilitates tumor‐suppressive cell competition by blocking toll‐mediated Yki activation in Drosophila. Current Biology 28 (11): 1756–1767.e6. DOI: 10.1016/j.cub.2018.04.022.

Kolahgar G, Suijkerbuijk SJE, Kucinski I, et al. (2015) Cell competition modifies adult stem cell and tissue population dynamics in a JAK‐STAT‐dependent manner. Developmental Cell 34 (3): 297–309. DOI: 10.1016/j.devcel.2015.06.010.

Lee CH, Kiparaki M, Blanco J, et al. (2018) A regulatory response to ribosomal protein mutations controls translation, growth, and cell competition. Developmental Cell 46 (4): 456–469.e4. DOI: 10.1016/j.devcel.2018.07.003.

Levayer R, Hauert B and Moreno E (2015) Cell mixing induced by myc is required for competitive tissue invasion and destruction. Nature 524 (7566): 476–480. DOI: 10.1038/nature14684.

Levayer R, Dupont C and Moreno E (2016) Tissue crowding induces caspase‐dependent competition for space. Current Biology 26 (5): 670–677. DOI: 10.1016/j.cub.2015.12.072.

Liu N, Matsumura H, Kato T, et al. (2019) Stem cell competition orchestrates skin homeostasis and ageing. Nature 568 (7752): 344–350. DOI: 10.1038/s41586‐019‐1085‐7.

Madan E, Gogna R and Moreno E (2018) Cell competition in development: information from flies and vertebrates. Current Opinion in Cell Biology 55: 150–157. DOI: 10.1016/j.ceb.2018.08.002.

Madan E, Pelham CJ, Nagane M, et al. (2019) Flower isoforms promote competitive growth in cancer. Nature 572: 260–264. DOI: 10.1038/s41586‐019‐1429‐3.

Martins VC, Busch K, Juraeva D, et al. (2014) Cell competition is a tumour suppressor mechanism in the thymus. Nature 509 (7501): 465–470. DOI: 10.1038/nature13317.

Marusyk A, Porter CC, Zaberezhnyy V and DeGregori J (2010) Irradiation selects for p53‐deficient hematopoietic progenitors. PLoS Biology 8 (3). DOI: 10.1371/journal.pbio.1000324.

Merino MM, Rhiner C, Lopez‐Gay JM, et al. (2015) Elimination of unfit cells maintains tissue health and prolongs lifespan. Cell 160 (3): 461–476. DOI: 10.1016/j.cell.2014.12.017.

Merino MM, Levayer R and Moreno E (2016) Survival of the fittest: essential roles of cell competition in development, aging, and cancer. Trends in Cell Biology 26 (10): 776–788. DOI: 10.1016/j.tcb.2016.05.009.

Meyer SN, Amoyel M, Bergantiños C, et al. (2014) An ancient defense system eliminates unfit cells from developing tissues during cell competition. Science 346 (6214). DOI: 10.1126/science.1258236.

Morata G and Ripoll P (1975) Minutes: mutants of Drosophila autonomously affecting cell division rate. Developmental Biology 42 (2): 211–221. DOI: 10.1016/0012‐1606(75)90330‐9.

Moreno E, Basler K and Morata G (2002) Cells compete for decapentaplegic survival factor to prevent apoptosis in Drosophila wing development. Nature 416 (6882): 755–759. DOI: 10.1038/416755a.

Moreno E and Basler K (2004) dMyc transforms cells into super‐competitors. Cell 117 (1): 117–129. DOI: 10.1016/S0092‐8674(04)00262‐4.

Moreno E and Rhiner C (2014) Darwin's multicellularity: from neurotrophic theories and cell competition to fitness fingerprints. Current Opinion in Cell Biology 31 (1): 16–22. DOI: 10.1016/j.ceb.2014.06.011.

Moreno E, Fernandez‐Marrero Y, Meyer P and Rhiner C (2015) Brain regeneration in Drosophila involves comparison of neuronal fitness. Current Biology 25 (7): 955–963. DOI: 10.1016/j.cub.2015.02.014.

Moreno E, Valon L, Levillayer F and Levayer R (2019) Competition for space induces cell elimination through compaction‐driven ERK downregulation. Current Biology 29 (1): 23–34.e8. DOI: 10.1016/j.cub.2018.11.007.

Portela M, Casas‐Tinto S, Rhiner C, et al. (2010) Drosophila SPARC is a self‐protective signal expressed by loser cells during cell competition. Developmental Cell 19 (4): 562–573. DOI: 10.1016/j.devcel.2010.09.004.

Rhiner C, López‐Gay JM, Soldini D, et al. (2010) Flower forms an extracellular code that reveals the fitness of a cell to its neighbors in Drosophila. Developmental Cell 18 (6): 985–998. DOI: 10.1016/j.devcel.2010.05.010.

Sancho M, Di‐Gregorio A, George N, et al. (2013) Competitive interactions eliminate unfit embryonic stem cells at the onset of differentiation. Developmental Cell 26 (1): 19–30. DOI: 10.1016/j.devcel.2013.06.012.

Sasaki A, Nagatake T, Egami R, et al. (2018) Obesity suppresses cell‐competition‐mediated apical elimination of Ras V12‐transformed cells from epithelial tissues. Cell Reports 23 (4): 974–982. DOI: 10.1016/j.celrep.2018.03.104.

Shakiba N and Zandstra PW (2017) Engineering cell fitness: lessons for regenerative medicine. Current Opinion in Biotechnology 47: 7–15. DOI: 10.1016/j.copbio.2017.05.005.

Stratton MR, Campbell PJ and Futreal PA (2009) The cancer genome. Nature 458 (7239): 719–724. DOI: 10.1038/nature07943.

Vaughen J and Igaki T (2016) Slit‐robo repulsive signaling extrudes tumorigenic cells from epithelia. Developmental Cell 39 (6): 683–695. DOI: 10.1016/j.devcel.2016.11.015.

Vincent JP, Kolahgar G, Gagliardi M and Piddini E (2011) Steep differences in wingless signaling trigger Myc‐independent competitive cell interactions. Developmental Cell 21 (2): 366–374. DOI: 10.1016/j.devcel.2011.06.021.

Wagstaff L, Goschorska M, Kozyrska K, et al. (2016) Mechanical cell competition kills cells via induction of lethal p53 levels. Nature Communications 7. DOI: 10.1038/ncomms11373.

Yamamoto M, Ohsawa S, Kunimasa K and Igaki T (2017) The ligand Sas and its receptor PTP10D drive tumour‐suppressive cell competition. Nature 542 (7640): 246–250. DOI: 10.1038/nature21033.

Zhang G, Xie Y, Zhou Y, et al. (2017) p53 pathway is involved in cell competition during mouse embryogenesis. Proceedings of the National Academy of Sciences of the United States of America 114 (3): 498–503. DOI: 10.1073/pnas.1617414114.

Further Reading

Baker NE (2017) Mechanisms of cell competition emerging from Drosophila studies. Current Opinion in Cell Biology 48: 40–46. DOI: 10.1016/j.ceb.2017.05.002.

Díaz‐Díaz C and Torres M (2019) Insights into the quantitative and dynamic aspects of cell competition. Current Opinion in Cell Biology 60: 68–74. DOI: 10.1016/j.ceb.2019.04.003.

Gutiérrez‐Martínez A, Sew WQG, Molano‐Fernández M, Carretero‐Junquera M and Herranz H (2019) Mechanisms of oncogenic cell competition–Paths of victory. Seminars in Cancer Biology: 1–9. DOI: 10.1016/j.semcancer.2019.05.015.

Levayer R and Moreno E (2016) How to be in a good shape? The influence of clone morphology on cell competition. Communicative and Integrative Biology 9 (1): 1–4. DOI: 10.1080/19420889.2015.1102806.

Nagata R and Igaki T (2018) Cell competition: emerging mechanisms to eliminate neighbors. Development Growth and Differentiation 60 (9): 522–530. DOI: 10.1111/dgd.12575.

Tonnessen‐Murray CA, Lozano G and Jackson JG (2017) The regulation of cellular functions by the p53 protein: cellular senescence. Cold Spring Harbor Perspectives in Medicine 7 (2): 1–14.

Vishwakarma M and Piddini E (2020) Outcompeting cancer. Nature Reviews Cancer 20: 187–198. DOI: 10.1038/s41568‐019‐0231‐8.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Costa, Catarina Marçal, Brás‐Pereira, Catarina, and Moreno, Eduardo(Dec 2020) Cell Competition. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0028476]