Advertisement

Drosophila Models of Cell Polarity and Cell Competition in Tumourigenesis

  • Natasha Fahey-Lozano
  • John E. La Marca
  • Marta Portela
  • Helena E. RichardsonEmail author
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1167)

Abstract

Cell competition is an important surveillance mechanism that measures relative fitness between cells in a tissue during development, homeostasis, and disease. Specifically, cells that are “less fit” (losers) are actively eliminated by relatively “more fit” (winners) neighbours, despite the less fit cells otherwise being able to survive in a genetically uniform tissue. Originally described in the epithelial tissues of Drosophila larval imaginal discs, cell competition has since been shown to occur in other epithelial and non-epithelial Drosophila tissues, as well as in mammalian model systems. Many genes and signalling pathways have been identified as playing conserved roles in the mechanisms of cell competition. Among them are genes required for the establishment and maintenance of apico-basal cell polarity: the Crumbs/Stardust/Patj (Crb/Sdt/Patj), Bazooka/Par-6/atypical Protein Kinase C (Baz/Par-6/aPKC), and Scribbled/Discs large 1/Lethal (2) giant larvae (Scrib/Dlg1/L(2)gl) modules. In this chapter, we describe the concepts and mechanisms of cell competition, with emphasis on the relationship between cell polarity proteins and cell competition, particularly the Scrib/Dlg1/L(2)gl module, since this is the best described module in this emerging field.

Keywords

Cell competition Cell polarity Drosophila Scrib D1g1 L(2)gl Hippo Myc PTP10D Sas Toll Flower Jak/Stat JNK TNF Caspase EGFR Ras 

Notes

Acknowledgements

JELM is supported by Australian Research Council (Grant DP170102549), NFL is supported by a La Trobe University PhD student scholarship, and HER is supported by funds from the School for Molecular Science at La Trobe University.

References

  1. 1.
    Abrams JM (2002) Competition and compensation: coupled to death in development and cancer. Cell 110:403–406PubMedCrossRefGoogle Scholar
  2. 2.
    Agrawal N, Joshi S, Kango M, Saha D, Mishra A, Sinha P (1995) Epithelial hyperplasia of imaginal discs induced by mutations in Drosophila tumor suppressor genes: growth and pattern formation in genetic mosaics. Dev Biol 169:387–398PubMedCrossRefGoogle Scholar
  3. 3.
    Alpar L, Bergantiños C, Johnston LA (2018) Spatially restricted regulation of Spätzle/toll signaling during cell competition. Dev Cell 46:706–719PubMedCrossRefGoogle Scholar
  4. 4.
    Andersen DS, Colombani J, Palmerini V, Chakrabandhu K, Boone E, Röthlisberger M, Toggweiler J, Basler K, Mapelli M, Hueber A-O, Léopold P (2015) The Drosophila TNF receptor Grindelwald couples loss of cell polarity and neoplastic growth. Nature 522:482–486PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Archibald A, Al-Masri M, Liew-Spilger A, McCaffrey L (2015) Atypical protein kinase C induces cell transformation by disrupting Hippo/Yap signaling. Mol Biol Cell 26:3578–3595PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Baker NE (2017) Mechanisms of cell competition emerging from Drosophila studies. Curr Opin Cell Biol 48:40–46PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Ballesteros-Arias L, Saavedra V, Morata G (2013) Cell competition may function either as tumour-suppressing or as tumour-stimulating factor in Drosophila. Oncogene 33:4377–4384PubMedCrossRefGoogle Scholar
  8. 8.
    Bilder D (2004) Epithelial polarity and proliferation control: links from the Drosophila neoplastic tumor suppressors. Genes Dev 18:1909–1925CrossRefGoogle Scholar
  9. 9.
    Bilder D, Li M, Perrimon N (2000) Cooperative regulation of cell polarity and growth by Drosophila tumor suppressors. Science 289:113–116PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Bondar T, Medzhitov R (2010) p53-mediated hematopoietic stem and progenitor cell competition. Cell Stem Cell 6:309–322PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Brennecke J, Hipfner DR, Stark A, Russell RB, Cohen SM (2003) bantam encodes a developmentally regulated microRNA that controls cell proliferation and regulates the Proapoptotic gene hid in Drosophila. Cell 113:25–36PubMedCrossRefGoogle Scholar
  12. 12.
    Brose K, Tessier-Lavigne M (2000) Slit proteins: key regulators of axon guidance, axonal branching, and cell migration. Curr Opin Neurobiol 10:95–102PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Brumby AM, Richardson HE (2003) scribble mutants cooperate with oncogenic Ras or Notch to cause neoplastic overgrowth in Drosophila. EMBO J 22:5769PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Bunker BD, Nellimoottil TT, Boileau RM, Classen AK, Bilder D (2015) The transcriptional response to tumorigenic polarity loss in Drosophila. elife 4:e03189PubMedCentralCrossRefPubMedGoogle Scholar
  15. 15.
    Cao F, Miao Y, Xu K, Liu P (2015) Lethal (2) Giant larvae: an indispensable regulator of cell polarity and Cancer development. Int J Biol Sci 11:380–389PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Caria S, Magtoto CM, Samiei T, Portela M, Lim KYB, How JY, Stewart BZ, Humbert PO, Richardson HE, Kvansakul M (2018) Drosophila melanogaster Guk-holder interacts with the scribbled PDZ1 domain and regulates epithelial development with scribbled and discs large. J Biol Chem 293:4519–4531PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Casas-Tintó S, Ferrús A (under review) Troponin-I localizes selected apico-basal cell polarity signals. bioRxiv, pp 1–9Google Scholar
  18. 18.
    Casas-Tintó S, Lolo F-N, Moreno E (2015) Active JNK-dependent secretion of Drosophila Tyrosyl-tRNA synthetase by loser cells recruits haemocytes during cell competition. Nat Commun 6:1–12Google Scholar
  19. 19.
    Casas-Tintó S, Maraver A, Serrano M, Ferrús A (2016) Troponin-I enhances and is required for oncogenic overgrowth. Oncotarget 7:52631–52642PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Chen C-L, Gajewski KM, Hamaratoglu F, Bossuyt W, Sansores-Garcia L, Tao C, Halder G (2010) The apical-basal cell polarity determinant crumbs regulates hippo signaling in Drosophila. Proc Natl Acad Sci U S A 107:15810–15815PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Chen CL, Schroeder MC, Kango-Singh M, Tao C, Halder G (2012) Tumor suppression by cell competition through regulation of the hippo pathway. Proc Natl Acad Sci U S A 109:484–489PubMedCrossRefGoogle Scholar
  22. 22.
    Clavería C, Giovinazzo G, Sierra R, Torres M (2013) Myc-driven endogenous cell competition in the early mammalian embryo. Nature 500:39–44PubMedCrossRefGoogle Scholar
  23. 23.
    Clavería C, Torres M (2016) Cell competition: mechanisms and physiological roles. Annu Rev Cell Dev Biol 32:411–439CrossRefGoogle Scholar
  24. 24.
    Cordero JB, Macagno JP, Stefanatos RK, Strathdee KE, Cagan RL, Vidal M (2010) Oncogenic Ras diverts a host TNF tumor suppressor activity into tumor promoter. Dev Cell 18:999–1011PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    de la Cova C, Abril M, Bellosta P, Gallant P, Johnston LA (2004) Drosophila Myc regulates organ size by inducing cell competition. Cell 117:107–116PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    de la Cova C, Johnston LA (2006) Myc in model organisms: a view from the flyroom. Semin Cancer Biol 16:303–312PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    de la Cova C, Senoo-Matsuda N, Ziosi M, Wu DC, Bellosta P, Quinzii CM, Johnston LA (2014) Supercompetitor status of Drosophila Myc cells requires p53 as a fitness sensor to reprogram metabolism and promote viability. Cell Metab 19:470–483PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    de Vreede G, Morrison HA, Houser AM, Boileau RM, Andersen DS, Colombani J, Bilder D (2018) A Drosophila tumor suppressor gene prevents tonic TNF signaling through receptor N-glycosylation. Dev Cell 45:595–605PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Di Giacomo S, Sollazzo M, de Biase D, Ragazzi M, Bellosta P, Pession A, Grifoni D (2017a) Human cancer cells signal their competitive fitness through MYC activity. Sci Rep 7:1–12CrossRefGoogle Scholar
  30. 30.
    Di Giacomo S, Sollazzo M, Paglia S, Grifoni D (2017b) MYC, cell competition, and cell death in cancer: the inseparable triad. Genes (Basel) 8:1–11Google Scholar
  31. 31.
    Díaz-Díaz C, Fernandez de Manuel L, Jimenez-Carretero D, Montoya MC, Clavería C, Torres M (2017) Pluripotency surveillance by Myc-driven competitive elimination of differentiating cells. Dev Cell 42:585–599PubMedCrossRefPubMedCentralGoogle Scholar
  32. 32.
    Doggett K, Grusche FA, Richardson HE, Brumby AM (2011) Loss of the Drosophila cell polarity regulator Scribbled promotes epithelial tissue overgrowth and cooperation with oncogenic Ras-Raf through impaired Hippo pathway signaling. BMC Dev Biol:11, 57PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Dow LE, Elsum IA, King CL, Kinross KM, Richardson HE, Humbert PO (2008) Loss of human scribble cooperates with H-Ras to promote cell invasion through deregulation of MAPK signalling. Oncogene 27:5988–6001PubMedCrossRefPubMedCentralGoogle Scholar
  34. 34.
    Eichenlaub T, Cohen SM, Herranz H (2016) Cell competition drives the formation of metastatic tumors in a Drosophila model of epithelial tumor formation. Curr Biol 26:419–427PubMedCrossRefGoogle Scholar
  35. 35.
    Elsum IA, Yates LL, Pearson HB, Phesse TJ, Long F, O’Donoghue R, Ernst M, Cullinane C, Humbert PO (2013) Scrib heterozygosity predisposes to lung cancer and cooperates with KRas hyperactivation to accelerate lung cancer progression in vivo. Oncogene 33:5523–5533PubMedCrossRefPubMedCentralGoogle Scholar
  36. 36.
    Enomoto M, Igaki T (2013) Src controls tumorigenesis via JNK-dependent regulation of the hippo pathway in Drosopihla. EMBO Rep 14:65–72PubMedCrossRefPubMedCentralGoogle Scholar
  37. 37.
    Enomoto M, Siow C, Igaki T (2018) Drosophila as a Cancer model. In: Yamaguchi M (ed) Drosophila models for human diseases. Springer Singapore, Singapore, pp 173–194CrossRefGoogle Scholar
  38. 38.
    Feigin ME, Akshinthala SD, Araki K, Rosenberg AZ, Muthuswamy LB, Martin B, Lehmann BD, Berman HK, Pietenpol JA, Cardiff RD, Muthuswamy SK (2014) Mislocalization of the cell polarity protein scribble promotes mammary tumorigenesis and is associated with basal breast Cancer. Cancer Res 74:3180–3194PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Fletcher GC, Lucas EP, Brain R, Tournier A, Thompson BJ (2012) Positive feedback and mutual antagonism combine to polarize crumbs in the Drosophila follicle cell epithelium. Curr Biol 22:1116–1122PubMedCrossRefGoogle Scholar
  40. 40.
    Froldi F, Ziosi M, Garoia F, Pession A, Grzeschik NA, Bellosta P, Strand D, Richardson HE, Pession A, Grifoni D (2010) The lethal giant larvae tumour suppressor mutation requires dMyc oncoprotein to promote clonal malignancy. BMC Biol 8:33PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Gateff E (1978) Malignant neoplasms of genetic origin in Drosophila melanogaster. Science 200:1448–1459PubMedCrossRefGoogle Scholar
  42. 42.
    Germani F, Hain D, Sternlicht D, Moreno E, Basler K (2018) The toll pathway inhibits tissue growth and regulates cell fitness in an infection-dependent manner. elife 7:e39939PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Gödde NJ, Pearson HB, Smith LK, Humbert PO (2014a) Dissecting the role of polarity regulators in cancer through the use of mouse models. Exp Cell Res 328:249–257PubMedCrossRefPubMedCentralGoogle Scholar
  44. 44.
    Gödde NJ, Sheridan JM, Smith LK, Pearson HB, Britt KL, Galea RC, Yates LL, Visvader JE, Humbert PO (2014b) Scribble modulates the MAPK/Fra1 pathway to disrupt luminal and ductal integrity and suppress tumour formation in the mammary gland. PLoS Genet 10:e1004323PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Govind S (2008) Innate immunity in Drosophila: pathogens and pathways. Insect Science 15:29–43PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Grzeschik NA, Amin N, Secombe J, Brumby AM, Richardson HE (2007) Abnormalities in cell proliferation and apico-basal cell polarity are separable in Drosophila lgl mutant clones in the developing eye. Dev Biol 311:106–123PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Grzeschik NA, Parsons LM, Allott ML, Harvey KF, Richardson HE (2010) Lgl, aPKC, and crumbs regulate the Salvador/Warts/Hippo pathway through two distinct mechanisms. Curr Biol 20:573–581PubMedCrossRefPubMedCentralGoogle Scholar
  48. 48.
    Hafezi Y, Bosch JA, Hariharan IK (2012) Differences in levels of the transmembrane protein crumbs can influence cell survival at clonal boundaries. Dev Biol 368:358–369PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674CrossRefGoogle Scholar
  50. 50.
    Harvey KF, Pfleger CM, Hariharan IK (2003) The Drosophila Mst Ortholog, hippo, restricts growth and cell proliferation and promotes apoptosis. Cell 114:457–467PubMedCrossRefGoogle Scholar
  51. 51.
    Hogan C, Dupré-Crochet S, Norman M, Kajita M, Zimmermann C, Pelling AE, Piddini E, Baena-López LA, Vincent J-P, Itoh Y, Hosoya H, Pichaud F, Fujita Y (2009) Characterization of the interface between normal and transformed epithelial cells. Nat Cell Biol 11:460–467PubMedCrossRefPubMedCentralGoogle Scholar
  52. 52.
    Humbert PO, Grzeschik NA, Brumby AM, Galea R, Elsum I, Richardson HE (2008) Control of tumourigenesis by the Scribble/Dlg/Lgl polarity module. Oncogene 27:6888–6907CrossRefGoogle Scholar
  53. 53.
    Humbert PO, Russell SM, Smith L, Richardson HE (2015) The scribble–Dlg–Lgl module in cell polarity regulation. In: Cell Polarity 1, chapter 4. Springer, Cham, pp 65–111Google Scholar
  54. 54.
    Igaki T, Kanda H, Yamamoto-Goto Y, Kanuka H, Kuranaga E, Aigaki T, Miura M (2002) Eiger, a TNF superfamily ligand that triggers the Drosophila JNK pathway. EMBO J 21:3009PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Igaki T, Pagliarini RA, Xu T (2006) Loss of cell polarity drives tumor growth and invasion through JNK activation in Drosophila. Curr Biol 16:1139–1146CrossRefGoogle Scholar
  56. 56.
    Igaki T, Pastor-Pareja JC, Aonuma H, Miura M, Xu T (2009) Intrinsic tumor suppression and epithelial maintenance by endocytic activation of Eiger/TNF signaling in Drosophila. Dev Cell 16:458–465PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Johnston LA, Prober DA, Edgar BA, Eisenman RN, Gallant P (1999) Drosophila myc regulates cellular growth during development. Cell 98:779–790PubMedCrossRefPubMedCentralGoogle Scholar
  58. 58.
    Kajita M, Fujita Y (2015) EDAC: epithelial defence against cancer—cell competition between normal and transformed epithelial cells in mammals. The Journal of Biochemistry 158:15–23PubMedCrossRefPubMedCentralGoogle Scholar
  59. 59.
    Kajita M, Hogan C, Harris AR, Dupre-Crochet S, Itasaki N, Kawakami K, Charras G, Tada M, Fujita Y (2010) Interaction with surrounding normal epithelial cells influences signalling pathways and behaviour of Src-transformed cells. J Cell Sci 123:171–180PubMedCrossRefPubMedCentralGoogle Scholar
  60. 60.
    Kale A, Li W, Lee CH, Baker NE (2015) Apoptotic mechanisms during competition of ribosomal protein mutant cells: roles of the initiator caspases Dronc and dream/Strica. Cell Death Differ 22:1300–1312PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Kapil S, Sharma BK, Patil M, Elattar S, Yuan J, Hou SX, Kolhe R, Satyanarayana A (2017) The cell polarity protein Scrib functions as a tumor suppressor in liver cancer. Oncotarget 8:26515–26531PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Katsukawa M, Ohsawa S, Zhang L, Yan Y, Igaki T (2018) Serpin facilitates tumor-suppressive cell competition by blocking toll-mediated Yki activation in Drosophila. Curr Biol 28:1756–1767PubMedCrossRefGoogle Scholar
  63. 63.
    Kon S, Ishibashi K, Katoh H, Kitamoto S, Shirai T, Tanaka S, Kajita M, Ishikawa S, Yamauchi H, Yako Y, Kamasaki T, Matsumoto T, Watanabe H, Egami R, Sasaki A, Nishikawa A, Kameda I, Maruyama T, Narumi R, Morita T, Sasaki Y, Enoki R, Honma S, Imamura H, Oshima M, Soga T, Miyazaki J, Duchen MR, Nam J-M, Onodera Y, Yoshioka S, Kikuta J, Ishii M, Imajo M, Nishida E, Fujioka Y, Ohba Y, Sato T, Fujita Y (2017) Cell competition with normal epithelial cells promotes apical extrusion of transformed cells through metabolic changes. Nat Cell Biol 19:530–541PubMedCrossRefGoogle Scholar
  64. 64.
    Kongsuwan K, Yu Q, Vincent A, Frisardi MC, Rosbash M, Lengyel JA, Merriam J (1985) A Drosophila Minute gene encodes a ribosomal protein. Nature 317:555–558PubMedCrossRefGoogle Scholar
  65. 65.
    La Fortezza M, Schenk M, Cosolo A, Kolybaba A, Grass I, Classen AK (2016) JAK/STAT signalling mediates cell survival in response to tissue stress. Development 143:2907–2919PubMedCrossRefGoogle Scholar
  66. 66.
    Leong GR, Goulding KR, Amin N, Richardson HE, Brumby AM (2009) scribble mutants promote aPKC and JNK-dependent epithelial neoplasia independently of Crumbs. BMC Biol 7:62PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Levayer R, Dupont C, Moreno E (2016) Tissue crowding induces caspase-dependent competition for space. Curr Biol 26:670–677PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Ling C, Zheng Y, Yin F, Yu J, Huang J, Hong Y, Wu S, Pan D (2010) The apical transmembrane protein crumbs functions as a tumor suppressor that regulates hippo signaling by binding to expanded. Proc Natl Acad Sci U S A 107:10532–10537PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Lolo F-N, Casas-Tintó S, Moreno E (2012) Cell competition time line: winners kill losers, which are extruded and engulfed by Hemocytes. Cell Rep 2:526–539PubMedCrossRefGoogle Scholar
  70. 70.
    Lolo F-N, Tintó SC, Moreno E (2013) How winner cells cause the demise of loser cells. BioEssays 35:348–353PubMedCrossRefGoogle Scholar
  71. 71.
    Lu H, Bilder D (2005) Endocytic control of epithelial polarity and proliferation in Drosophila. Nat Cell Biol 7:1232–1239CrossRefGoogle Scholar
  72. 72.
    Ma X, Chen Y, Zhang S, Xu W, Shao Y, Yang Y, Li W, Li M, Xue L (2016) Rho1–Wnd signaling regulates loss-of-cell polarity-induced cell invasion in Drosophila. Oncogene 35:846–855PubMedCrossRefGoogle Scholar
  73. 73.
    Ma X, Guo X, Richardson HE, Xu T, Xue L (2018) POSH regulates hippo signaling through ubiquitin-mediated expanded degradation. Proc Natl Acad Sci U S A 115:2150–2155PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Madan E, Gogna R, Moreno E (2018) Cell competition in development: information from flies and vertebrates. Curr Opin Cell Biol 55:150–157PubMedCrossRefGoogle Scholar
  75. 75.
    Mamada H, Sato T, Ota M, Sasaki H (2015) Cell competition in mouse NIH3T3 embryonic fibroblasts is controlled by the activity of Tead family proteins and Myc. J Cell Sci 128:790–803PubMedCrossRefGoogle Scholar
  76. 76.
    Marinari E, Mehonic A, Curran S, Gale J, Duke T, Baum B (2012) Live-cell delamination counterbalances epithelial growth to limit tissue overcrowding. Nature 484:542–545PubMedCrossRefGoogle Scholar
  77. 77.
    Martins VC, Busch K, Juraeva D, Blum C, Ludwig C, Rasche V, Lasitschka F, Mastitsky SE, Brors B, Hielscher T, Fehling HJ, Rodewald H-R (2014) Cell competition is a tumour suppressor mechanism in the thymus. Nature 509:465–470PubMedCrossRefGoogle Scholar
  78. 78.
    Marygold SJ, Roote J, Reuter G, Lambertsson A, Ashburner M, Millburn GH, Harrison PM, Yu Z, Kenmochi N, Kaufman TC, Leevers SJ, Cook KR (2007) The ribosomal protein genes and Minute loci of Drosophila melanogaster. Genome Biol 8:R216PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Mathew D, Gramates LS, Packard M, Thomas U, Bilder D, Perrimon N, Gorczyca M, Budnik V (2002) Recruitment of scribble to the synaptic scaffolding complex requires GUK-holder, a novel DLG binding protein. Curr Biol 12:531–539PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Menendez J, Perez-Garijo A, Calleja M, Morata G (2010) A tumor-suppressing mechanism in Drosophila involving cell competition and the hippo pathway. Proc Natl Acad Sci U S A 107:14651–14656PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Menut L, Vaccari T, Dionne H, Hill J, Wu G, Bilder D (2007) A mosaic genetic screen for Drosophila neoplastic tumor suppressor genes based on defective pupation. Genetics 177:1667–1677PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Merino MM, Levayer R, Moreno E (2016) Survival of the fittest: essential roles of cell competition in development, aging, and Cancer. Trends Cell Biol 26:776–788PubMedCrossRefGoogle Scholar
  83. 83.
    Merino MM, Rhiner C, López-Gay JM, Buechel D, Hauert B, Moreno E (2015) Elimination of unfit cells maintains tissue health and prolongs lifespan. Cell 160:461–476PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Merino MM, Rhiner C, Portela M, Moreno E (2013) “Fitness fingerprints” mediate physiological culling of unwanted neurons in Drosophila. Curr Biol 23:1300–1309PubMedCrossRefGoogle Scholar
  85. 85.
    Meyer SN, Amoyel M, Bergantinos C, de la Cova C, Schertel C, Basler K, Johnston LA (2014) An ancient defense system eliminates unfit cells from developing tissues during cell competition. Science 346:1258236PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Misra JR, Irvine KD (2018) The hippo signaling network and its biological functions. Annu Rev Genet 52:65–87PubMedCrossRefGoogle Scholar
  87. 87.
    Moberg KH, Schelble S, Burdick SK, Hariharan IK (2005) Mutations in erupted, the Drosophila Ortholog of mammalian tumor susceptibility gene 101, elicit non-cell-autonomous overgrowth. Dev Cell 9:699–710CrossRefGoogle Scholar
  88. 88.
    Morata G, Ripoll P (1975) Minutes: mutants of Drosophila autonomously affecting cell division rate. Dev Biol 42:211–221PubMedCrossRefGoogle Scholar
  89. 89.
    Moreno E, Basler K (2004) dMyc transforms cells into super-competitors. Cell 117:117–129PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Moreno E, Basler K, Morata G (2002a) Cells compete for decapentaplegic survival factor to prevent apoptosis in Drosophila wing development. Nature 416:755–759PubMedCrossRefGoogle Scholar
  91. 91.
    Moreno E, Yan M, Basler K (2002b) Evolution of TNF signaling mechanisms: JNK-dependent apoptosis triggered by Eiger, the Drosophila homolog of the TNF superfamily. Curr Biol 12:1263–1268PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Muthuswamy SK, Xue B (2012) Cell polarity as a regulator of Cancer cell behavior plasticity. Annu Rev Cell Dev Biol 28:599–625PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Muzzopappa M, Murcia L, Milán M (2017) Feedback amplification loop drives malignant growth in epithelial tissues. Proc Natl Acad Sci U S A 114:7291–7300CrossRefGoogle Scholar
  94. 94.
    Nahvi A, Shoemaker CJ, Green R (2009) An expanded seed sequence definition accounts for full regulation of the hid 3′ UTR by bantam miRNA. RNA (New York, NY) 15:814–822CrossRefGoogle Scholar
  95. 95.
    Neto-Silva RM, de Beco S, Johnston LA (2010) Evidence for a growth-stabilizing regulatory feedback mechanism between Myc and Yorkie, the Drosophila homolog of yap. Dev Cell 19:507–520PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Norman M, Wisniewska KA, Lawrenson K, Garcia-Miranda P, Tada M, Kajita M, Mano H, Ishikawa S, Ikegawa M, Shimada T, Fujita Y (2012) Loss of scribble causes cell competition in mammalian cells. J Cell Sci 125:59–66PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Oertel M, Menthena A, Dabeva MD, Shafritz DA (2006) Cell competition leads to a high level of normal liver reconstitution by transplanted fetal liver stem/progenitor cells. Gastroenterology 130:507–520PubMedCrossRefGoogle Scholar
  98. 98.
    Oh H, Irvine KD (2010) Yorkie: the final destination of hippo signaling. Trends Cell Biol 20:410–417PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Ohsawa S, Sugimura K, Takino K, Xu T, Miyawaki A, Igaki T (2011) Elimination of oncogenic neighbors by JNK-mediated engulfment in Drosophila. Dev Cell 20:315–328CrossRefGoogle Scholar
  100. 100.
    Ohshiro T, Yagami T, Zhang C, Matsuzaki F (2000) Role of cortical tumour-suppressor proteins in asymmetric division of Drosophila neuroblast. Nature 408:593–596PubMedCrossRefGoogle Scholar
  101. 101.
    Oliver ER, Saunders TL, Tarle SA, Glaser T (2004) Ribosomal protein L24 defect in belly spot and tail (Bst), a mouse Minute. Development 131:3907–3920PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Pagliarini RA, Xu T (2003) A genetic screen in Drosophila for metastatic behavior. Science 302:1227–1231PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Parsons LM, Portela M, Grzeschik NA, Richardson HE (2014) Lgl regulates notch signaling via endocytosis, independently of the apical aPKC-Par6-Baz polarity complex. Curr Biol 24:2073–2084PubMedCrossRefGoogle Scholar
  104. 104.
    Pearson HB, McGlinn E, Phesse TJ, Schlüter H, Srikumar A, Gödde NJ, Woelwer CB, Ryan A, Phillips WA, Ernst M, Kaur P, Humbert PO (2015) The polarity protein Scrib mediates epidermal development and exerts a tumor suppressive function during skin carcinogenesis. Mol Cancer 14:169PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Pearson HB, Perez-Mancera PA, Dow LE, Ryan A, Tennstedt P, Bogani D, Elsum IA, Greenfield A, Tuveson DA, Simon R, Humbert PO (2011) SCRIB expression is deregulated in human prostate cancer, and its deficiency in mice promotes prostate neoplasia. J Clin Invest 121:4257–4267PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Peng C-Y, Manning L, Albertson R, Doe CQ (2000) The tumour-suppressor genes lgl and dlg regulate basal protein targeting in Drosophila neuroblasts. Nature 408:596–600PubMedCrossRefGoogle Scholar
  107. 107.
    Portela M, Casas-Tinto S, Rhiner C, López-Gay JM, Domínguez O, Soldini D, Moreno E (2010) Drosophila SPARC is a self-protective signal expressed by loser cells during cell competition. Dev Cell 19:562–573PubMedCrossRefGoogle Scholar
  108. 108.
    Rejon C, Al-Masri M, McCaffrey L (2016) Cell polarity proteins in breast Cancer progression. J Cell Biochem 117:2215–2223PubMedCrossRefGoogle Scholar
  109. 109.
    Rhiner C, López-Gay JM, Soldini D, Casas-Tinto S, Martín FA, Lombardía L, Moreno E (2010) Flower forms an extracellular code that reveals the fitness of a cell to its neighbors in Drosophila. Dev Cell 18:985–998PubMedCrossRefGoogle Scholar
  110. 110.
    Ribeiro P, Holder M, Frith D, Snijders AP, Tapon N (2014) Crumbs promotes expanded recognition and degradation by the SCFSlimb/β-TrCP ubiquitin ligase. Proc Natl Acad Sci U S A 111:1980–1989CrossRefGoogle Scholar
  111. 111.
    Richardson HE, Portela M (2016) Robo-enabled tumor cell extrusion. Dev Cell 39:629–631PubMedCrossRefGoogle Scholar
  112. 112.
    Richardson HE, Portela M (2018) Modelling cooperative tumorigenesis in Drosophila. Biomed Res Int 2018, pp 1–29CrossRefGoogle Scholar
  113. 113.
    Rives-Quinto N, Franco M, de Torres-Jurado A, Carmena A (2017) Synergism between canoe and scribble mutations causes tumor-like overgrowth via Ras activation in neural stem cells and epithelia. Development 144:2570–2583PubMedCrossRefGoogle Scholar
  114. 114.
    Robinson BS, Huang J, Hong Y, Moberg KH (2010) Crumbs regulates Salvador/warts/hippo signaling in Drosophila via the FERM-domain protein expanded. Curr Biol 20:582–590PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Rodrigues AB, Zoranovic T, Ayala-Camargo A, Grewal S, Reyes-Robles T, Krasny M, Wu DC, Johnston LA, Bach EA (2012) Activated STAT regulates growth and induces competitive interactions independently of Myc, Yorkie, wingless and ribosome biogenesis. Development 139:4051–4061PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Sakakibara J, Sakakibara M, Shiina N, Fujimori T, Okubo Y, Fujisaki K, Nagashima T, Sangai T, Nakatani Y, Miyazaki M (2017) Expression of cell polarity protein scribble differently affects prognosis in primary tumor and lymph node metastasis of breast cancer patients. Breast Cancer 24:393–399PubMedCrossRefGoogle Scholar
  117. 117.
    Sancho M, Di-Gregorio A, George N, Pozzi S, Sanchez JM, Pernaute B, Rodriguez TA (2013) Competitive interactions eliminate unfit embryonic stem cells at the onset of differentiation. Dev Cell 26:19–30PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Schroeder MC, Chen CL, Gajewski K, Halder G (2012) A non-cell-autonomous tumor suppressor role for Stat in eliminating oncogenic scribble cells. Oncogene 32:4471–4479PubMedCrossRefGoogle Scholar
  119. 119.
    Shlevkov E, Morata G (2011) A dp53/JNK-dependant feedback amplification loop is essential for the apoptotic response to stress in Drosophila. Cell Death Differ 19:451–460PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Shraiman BI (2005) Mechanical feedback as a possible regulator of tissue growth. Proc Natl Acad Sci U S A 102:3318–3323PubMedPubMedCentralCrossRefGoogle Scholar
  121. 121.
    Simpson P (1979) Parameters of cell competition in the compartments of the wing disc of Drosophila. Dev Biol 69:182–193PubMedCrossRefGoogle Scholar
  122. 122.
    Simpson P, Morata G (1981) Differential mitotic rates and patterns of growth in compartments in the Drosophila wing. Dev Biol 85:299–308PubMedCrossRefGoogle Scholar
  123. 123.
    Sollazzo M, Genchi C, Paglia S, Di Giacomo S, Pession A, de Biase D, Grifoni D (2018) High MYC levels favour multifocal carcinogenesis. Front Genet 9:1–15Google Scholar
  124. 124.
    Sotillos S, Díaz-Meco MT, Caminero E, Moscat J, Campuzano S (2004) DaPKC-dependent phosphorylation of crumbs is required for epithelial cell polarity in Drosophila. J Cell Biol 166:549–557PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Suijkerbuijk SJ, Kolahgar G, Kucinski I, Piddini E (2016) Cell competition drives the growth of intestinal adenomas in Drosophila. Curr Biol 26:428–438PubMedPubMedCentralCrossRefGoogle Scholar
  126. 126.
    Sun G, Irvine KD (2013) Ajuba family proteins link JNK to hippo signaling. Sci Signal 6:ra81PubMedCrossRefGoogle Scholar
  127. 127.
    Tamori Y, Bialucha CU, Tian A-G, Kajita M, Huang Y-C, Norman M, Harrison N, Poulton J, Ivanovitch K, Disch L, Liu T, Deng W-M, Fujita Y (2010) Involvement of Lgl and mahjong/VprBP in cell competition. PLoS Biol 8:1–10PubMedPubMedCentralCrossRefGoogle Scholar
  128. 128.
    Tapon N, Harvey KF, Bell DW, Wahrer DCR, Schiripo TA, Haber DA, Hariharan IK (2002) salvador promotes both cell cycle exit and apoptosis in Drosophila and is mutated in human Cancer cell lines. Cell 110:467–478PubMedCrossRefGoogle Scholar
  129. 129.
    Tepass U (2012) The apical polarity protein network in Drosophila epithelial cells: regulation of polarity, junctions, morphogenesis, cell growth, and survival. Annu Rev Cell Dev Biol 28:655–685PubMedCrossRefGoogle Scholar
  130. 130.
    Tepass U, Theres C, Knust E (1990) crumbs encodes an EGF-like protein expressed on apical membranes of Drosophila epithelial cells and required for organization of epithelia. Cell 61:787–799PubMedCrossRefGoogle Scholar
  131. 131.
    Thiery JP (2002) Epithelial–mesenchymal transitions in tumour progression. Nat Rev Cancer 2:442–454PubMedCrossRefGoogle Scholar
  132. 132.
    Thompson BJ, Mathieu J, Sung H-H, Loeser E, Rørth P, Cohen SM (2005) Tumor suppressor properties of the ESCRT-II complex component Vps25 in Drosophila. Dev Cell 9:711–720CrossRefGoogle Scholar
  133. 133.
    Tyler DM, Li W, Zhuo N, Pellock B, Baker NE (2007) Genes affecting cell competition in Drosophila. Genetics 175:643–657PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Uhlirova M, Jasper H, Bohmann D (2005) Non-cell-autonomous induction of tissue overgrowth by JNK/Ras cooperation in a Drosophila tumor model. Proc Natl Acad Sci U S A 102:13123–13128PubMedPubMedCentralCrossRefGoogle Scholar
  135. 135.
    Vaccari T, Bilder D (2005) The Drosophila tumor suppressor vps25 prevents nonautonomous Overproliferation by regulating notch trafficking. Dev Cell 9:687–698PubMedPubMedCentralCrossRefGoogle Scholar
  136. 136.
    Valanne S, Wang J-H, Rämet M (2011) The Drosophila toll signaling pathway. J Immunol 186:649–656PubMedCrossRefPubMedCentralGoogle Scholar
  137. 137.
    Vaughen J, Igaki T (2016) Slit-Robo repulsive signaling extrudes tumorigenic cells from epithelia. Dev Cell 39:683–695PubMedPubMedCentralCrossRefGoogle Scholar
  138. 138.
    Vidal M (2010) The dark side of fly TNF. Cell Cycle 9:3851–3856PubMedPubMedCentralCrossRefGoogle Scholar
  139. 139.
    Vidal M, Larson DE, Cagan RL (2006) Csk-deficient boundary cells are eliminated from Normal Drosophila epithelia by exclusion, migration, and apoptosis. Dev Cell 10:33–44PubMedCrossRefGoogle Scholar
  140. 140.
    Villa Del Campo C, Claveria C, Sierra R, Torres M (2014) Cell competition promotes phenotypically silent cardiomyocyte replacement in the mammalian heart. Cell Rep 8:1741–1751PubMedCrossRefGoogle Scholar
  141. 141.
    Vincent J-P, Fletcher AG, Baena-Lopez LA (2013) Mechanisms and mechanics of cell competition in epithelia. Nat Rev Mol Cell Biol 14:581–591PubMedCrossRefGoogle Scholar
  142. 142.
    Vincent JP, Kolahgar G, Gagliardi M, Piddini E (2011) Steep differences in wingless signaling trigger Myc-independent competitive cell interactions. Dev Cell 21:366–374PubMedPubMedCentralCrossRefGoogle Scholar
  143. 143.
    Wagstaff L, Goschorska M, Kozyrska K, Duclos G, Kucinski I, Chessel A, Hampton-O’Neil L, Bradshaw CR, Allen GE, Rawlins EL, Silberzan P, Carazo Salas RE, Piddini E (2016) Mechanical cell competition kills cells via induction of lethal p53 levels. Nat Commun 7:1–14Google Scholar
  144. 144.
    Wodarz A (2000) Tumor suppressors: linking cell polarity and growth control. Curr Biol 10:624–626CrossRefGoogle Scholar
  145. 145.
    Wu M, Pastor-Pareja JC, Xu T (2010) Interaction between RasV12 and scribbled clones induces tumour growth and invasion. Nature 463:545–548PubMedPubMedCentralCrossRefGoogle Scholar
  146. 146.
    Yamamoto M, Ohsawa S, Kunimasa K, Igaki T (2017) The ligand Sas and its receptor PTP10D drive tumour-suppressive cell competition. Nature 542:246–250CrossRefGoogle Scholar
  147. 147.
    Yamashita K, Ide M, Furukawa KT, Suzuki A, Hirano H, Ohno S (2015) Tumor suppressor protein Lgl mediates G1 cell cycle arrest at high cell density by forming an Lgl-VprBP-DDB1 complex. Mol Biol Cell 26:2426–2438PubMedPubMedCentralCrossRefGoogle Scholar
  148. 148.
    Zhang S, Feng Y, Narayan O, Zhao L-J (2001) Cytoplasmic retention of HIV-1 regulatory protein Vpr by protein-protein interaction with a novel human cytoplasmic protein VprBP. Gene 263:131–140PubMedCrossRefGoogle Scholar
  149. 149.
    Ziosi M, Baena-López LA, Grifoni D, Froldi F, Pession A, Garoia F, Trotta V, Bellosta P, Cavicchi S, Pession A (2010) dMyc functions downstream of Yorkie to promote the Supercompetitive behavior of hippo pathway mutant cells. PLoS Genet 6:e1001140PubMedPubMedCentralCrossRefGoogle Scholar
  150. 150.
    Zoranovic T, Grmai L, Bach EA (2013) Regulation of proliferation, cell competition, and cellular growth by the Drosophila JAK-STAT pathway. JAK-STAT 2:e25408PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Natasha Fahey-Lozano
    • 1
  • John E. La Marca
    • 1
  • Marta Portela
    • 2
  • Helena E. Richardson
    • 1
    Email author
  1. 1.Department of Biochemistry and Genetics, La Trobe Institute for Molecular ScienceLa Trobe UniversityMelbourneAustralia
  2. 2.Department of Molecular, Cellular and Developmental NeurobiologyCajal Institute (CSIC)MadridSpain

Personalised recommendations