Using Drosophila Models and Tools to Understand the Mechanisms of Novel Human Cancer Driver Gene Function

  • Santiago Nahuel VillegasEmail author
  • Dolors Ferres-MarcoEmail author
  • María Domínguez
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1167)


The formation, overgrowth and metastasis of tumors comprise a complex series of cellular and molecular events resulting from the combined effects of a variety of aberrant signaling pathways, mutations, and epigenetic alterations. Modeling this complexity in vivo requires multiple genes to be manipulated simultaneously, which is technically challenging. Here, we analyze how Drosophila research can further contribute to identifying pathways and elucidating mechanisms underlying novel cancer driver (risk) genes associated with tumor growth and metastasis in humans.


Cancer driver genes Drosophila Cancer genetic toolkit 



Work in the authors laboratory is supported by the Spanish Ministry of Economy and Competitiveness and co-financed by FEDER funds (BFU2015-64239-R, the Spanish State Research Agency, through the “Severo Ochoa” Program for Centers of Excellence in R&D (SEV-2013-0317), the Scientific Foundation of the Spanish Association Against Cancer (AECC) (CICPF16001DOMÍ), and the Valencian Regional Government’s Prometeo Programme for research groups of excellence (PROMETEO/2017/146) to M.D.


  1. 1.
    Stark MB (1918) An hereditary tumor in the fruit Fly, Drosophila. Am Assoc Cancer Res J 3(3):279–301Google Scholar
  2. 2.
    Tan H, Bao J, Zhou X (2015) Genome-wide mutational spectra analysis reveals significant cancer-specific heterogeneity. Sci Rep 5:12566PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Gonzalez C (2013) Drosophila melanogaster: a model and a tool to investigate malignancy and identify new therapeutics. Nat Rev Cancer 13(3):172–183PubMedCrossRefPubMedCentralGoogle Scholar
  4. 4.
    Rudrapatna VA, Cagan RL, Das TK (2012) Drosophila cancer models. Dev Dyn 241(1):107–118PubMedCrossRefGoogle Scholar
  5. 5.
    Enomoto M, Siow C, Igaki T (2018) Drosophila as a Cancer model. Adv Exp Med Biol 1076:173–194CrossRefGoogle Scholar
  6. 6.
    Tipping M, Perrimon N (2014) Drosophila as a model for context-dependent tumorigenesis. J Cell Physiol 229(1):27–33PubMedPubMedCentralGoogle Scholar
  7. 7.
    Pastor-Pareja JC, Xu T (2013) Dissecting social cell biology and tumors using Drosophila genetics. Annu Rev Genet 47:51–74PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Bailey MH et al (2018) Comprehensive characterization of Cancer driver genes and mutations. Cell 174(4):1034–1035PubMedCrossRefPubMedCentralGoogle Scholar
  9. 9.
    Vogelstein B et al (2013) Cancer genome landscapes. Science 339(6127):1546–1558PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Kandoth C et al (2013) Mutational landscape and significance across 12 major cancer types. Nature 502(7471):333–339PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Bangi E et al (2016) Functional exploration of colorectal cancer genomes using Drosophila. Nat Commun 7:13615PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Morgan TH (1917) The theory of the gene. Am Nat 51:31CrossRefGoogle Scholar
  13. 13.
    Ellisen LW et al (1991) TAN-1, the human homolog of the Drosophila notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms. Cell 66(4):649–661PubMedCrossRefPubMedCentralGoogle Scholar
  14. 14.
    Bray SJ (2006) Notch signalling: a simple pathway becomes complex. Nat Rev Mol Cell Biol 7(9):678–689PubMedCrossRefPubMedCentralGoogle Scholar
  15. 15.
    Artavanis-Tsakonas S, Matsuno K, Fortini ME (1995) Notch signaling. Science 268(5208):225–232PubMedCrossRefGoogle Scholar
  16. 16.
    Dominguez M (2014) Oncogenic programmes and notch activity: an ‘organized crime’? Semin Cell Dev Biol 28:78–85PubMedCrossRefPubMedCentralGoogle Scholar
  17. 17.
    Lemmon MA, Schlessinger J (2010) Cell signaling by receptor tyrosine kinases. Cell 141(7):1117–1134PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Stephen AG et al (2014) Dragging ras back in the ring. Cancer Cell 25(3):272–281PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.
    Simon MA et al (1991) Ras1 and a putative guanine nucleotide exchange factor perform crucial steps in signaling by the sevenless protein tyrosine kinase. Cell 67(4):701–716PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Rubin GM et al (1997) Signal transduction downstream from Ras in Drosophila. Cold Spring Harb Symp Quant Biol 62:347–352PubMedCrossRefPubMedCentralGoogle Scholar
  21. 21.
    Perrimon N (1994) Signalling pathways initiated by receptor protein tyrosine kinases in Drosophila. Curr Opin Cell Biol 6(2):260–266PubMedCrossRefPubMedCentralGoogle Scholar
  22. 22.
    Wassarman DA, Therrien M, Rubin GM (1995) The Ras signaling pathway in Drosophila. Curr Opin Genet Dev 5(1):44–50PubMedCrossRefPubMedCentralGoogle Scholar
  23. 23.
    Karim FD, Rubin GM (1998) Ectopic expression of activated Ras1 induces hyperplastic growth and increased cell death in Drosophila imaginal tissues. Development 125(1):1–9PubMedGoogle Scholar
  24. 24.
    Pagliarini RA, Xu T (2003) A genetic screen in Drosophila for metastatic behavior. Science 302(5648):1227–1231PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Eerola I et al (2003) Capillary malformation-arteriovenous malformation, a new clinical and genetic disorder caused by RASA1 mutations. Am J Hum Genet 73(6):1240–1249PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Boon LM, Mulliken JB, Vikkula M (2005) RASA1: variable phenotype with capillary and arteriovenous malformations. Curr Opin Genet Dev 15(3):265–269PubMedCrossRefPubMedCentralGoogle Scholar
  27. 27.
    Wooderchak-Donahue WL et al (2018) Expanding the clinical and molecular findings in RASA1 capillary malformation-arteriovenous malformation. Eur J Hum Genet 26(10):1521–1536PubMedCrossRefPubMedCentralGoogle Scholar
  28. 28.
    Botella JA et al (2003) Deregulation of the Egfr/Ras signaling pathway induces age-related brain degeneration in the Drosophila mutant vap. Mol Biol Cell 14(1):241–250PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Kajiho H et al (2003) RIN3: a novel Rab5 GEF interacting with amphiphysin II involved in the early endocytic pathway. J Cell Sci 116(Pt 20):4159–4168PubMedCrossRefPubMedCentralGoogle Scholar
  30. 30.
    Schmid SL (2017) Reciprocal regulation of signaling and endocytosis: implications for the evolving cancer cell. J Cell Biol 216(9):2623–2632PubMedPubMedCentralGoogle Scholar
  31. 31.
    Schmukler E, Kloog Y, Pinkas-Kramarski R (2014) Ras and autophagy in cancer development and therapy. Oncotarget 5(3):577–586PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Cai W et al (2011) An evolutionarily conserved Rit GTPase-p38 MAPK signaling pathway mediates oxidative stress resistance. Mol Biol Cell 22(17):3231–3241PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Cai W, Andres DA (2014) mTORC2 is required for rit-mediated oxidative stress resistance. PLoS One 9(12):e115602PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Wagner EF, Nebreda AR (2009) Signal integration by JNK and p38 MAPK pathways in cancer development. Nat Rev Cancer 9(8):537–549PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Villegas SN et al (2018) PI3K/Akt cooperates with oncogenic notch by inducing nitric oxide-dependent inflammation. Cell Rep 22(10):2541–2549PubMedCrossRefGoogle Scholar
  36. 36.
    Williams JA et al (2001) A circadian output in Drosophila mediated by neurofibromatosis-1 and Ras/MAPK. Science 293(5538):2251–2256PubMedCrossRefGoogle Scholar
  37. 37.
    Kitajima S, Barbie DA (2018) RASA1/NF1-mutant lung Cancer: racing to the clinic? Clin Cancer Res 24(6):1243–1245PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Brumby AM, Richardson HE (2003) Scribble mutants cooperate with oncogenic Ras or notch to cause neoplastic overgrowth in Drosophila. EMBO J 22(21):5769–5779PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Zoranovic T et al (2018) A genome-wide Drosophila epithelial tumorigenesis screen identifies Tetraspanin 29Fb as an evolutionarily conserved suppressor of Ras-driven cancer. PLoS Genet 14(10):e1007688PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Ohsawa S et al (2012) Mitochondrial defect drives non-autonomous tumour progression through Hippo signalling in Drosophila. Nature 490(7421):547–551CrossRefGoogle Scholar
  41. 41.
    Igaki T, Pagliarini RA, Xu T (2006) Loss of cell polarity drives tumor growth and invasion through JNK activation in Drosophila. Curr Biol 16(11):1139–1146CrossRefGoogle Scholar
  42. 42.
    Stogios PJ et al (2005) Sequence and structural analysis of BTB domain proteins. Genome Biol 6(10):R82PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Steklov M et al (2018) Mutations in LZTR1 drive human disease by dysregulating RAS ubiquitination. Science 362(6419):1177–1182PubMedCrossRefPubMedCentralGoogle Scholar
  44. 44.
    Bigenzahn JW et al (2018) LZTR1 is a regulator of RAS ubiquitination and signaling. Science 362(6419):1171–1177PubMedCrossRefGoogle Scholar
  45. 45.
    Pae J et al (2017) GCL and CUL3 control the switch between cell lineages by mediating localized degradation of an RTK. Dev Cell 42(2):130–142. e7PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Tennessen JM et al (2011) The Drosophila estrogen-related receptor directs a metabolic switch that supports developmental growth. Cell Metab 13(2):139–148PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Liberti MV, Locasale JW (2016) The Warburg effect: how does it benefit Cancer cells? Trends Biochem Sci 41(3):211–218PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Deblois G, Giguere V (2013) Oestrogen-related receptors in breast cancer: control of cellular metabolism and beyond. Nat Rev Cancer 13(1):27–36PubMedCrossRefGoogle Scholar
  49. 49.
    Cohen MS, Hadjivassiliou H, Taunton J (2007) A clickable inhibitor reveals context-dependent autoactivation of p90 RSK. Nat Chem Biol 3(3):156–160PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Richards SA et al (2001) Characterization of regulatory events associated with membrane targeting of p90 ribosomal S6 kinase 1. Mol Cell Biol 21(21):7470–7480PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Akten B et al (2009) Ribosomal s6 kinase cooperates with casein kinase 2 to modulate the Drosophila circadian molecular oscillator. J Neurosci 29(2):466–475PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Tangredi MM, Ng FS, Jackson FR (2012) The C-terminal kinase and ERK-binding domains of Drosophila S6KII (RSK) are required for phosphorylation of the protein and modulation of circadian behavior. J Biol Chem 287(20):16748–16758PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Kim M et al (2006) Inhibition of ERK-MAP kinase signaling by RSK during Drosophila development. EMBO J 25(13):3056–3067PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Hu L et al (2014) Drosophila casein kinase 2 (CK2) promotes warts protein to suppress Yorkie protein activity for growth control. J Biol Chem 289(48):33598–33607PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Cho YY (2017) RSK2 and its binding partners in cell proliferation, transformation and cancer development. Arch Pharm Res 40(3):291–303PubMedCrossRefPubMedCentralGoogle Scholar
  56. 56.
    Thackeray JR et al (1998) Small wing encodes a phospholipase C-(gamma) that acts as a negative regulator of R7 development in Drosophila. Development 125(24):5033–5042PubMedPubMedCentralGoogle Scholar
  57. 57.
    Schlesinger A et al (2004) Small wing PLCgamma is required for ER retention of cleaved Spitz during eye development in Drosophila. Dev Cell 7(4):535–545PubMedCrossRefPubMedCentralGoogle Scholar
  58. 58.
    Murillo-Maldonado JM et al (2011) Insulin receptor-mediated signaling via phospholipase C-gamma regulates growth and differentiation in Drosophila. PLoS One 6(11):e28067PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Freeman RM Jr, Plutzky J, Neel BG (1992) Identification of a human src homology 2-containing protein-tyrosine-phosphatase: a putative homolog of Drosophila corkscrew. Proc Natl Acad Sci U S A 89(23):11239–11243PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Shi ZQ et al (2000) Molecular mechanism for the Shp-2 tyrosine phosphatase function in promoting growth factor stimulation of Erk activity. Mol Cell Biol 20(5):1526–1536PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Qu CK (2000) The SHP-2 tyrosine phosphatase: signaling mechanisms and biological functions. Cell Res 10(4):279–288PubMedCrossRefPubMedCentralGoogle Scholar
  62. 62.
    Prahallad A et al (2015) PTPN11 is a central node in intrinsic and acquired resistance to targeted Cancer drugs. Cell Rep 12(12):1978–1985PubMedCrossRefPubMedCentralGoogle Scholar
  63. 63.
    Breitkopf SB et al (2016) A cross-species study of PI3K protein-protein interactions reveals the direct interaction of P85 and SHP2. Sci Rep 6:20471PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Cully M et al (2006) Beyond PTEN mutations: the PI3K pathway as an integrator of multiple inputs during tumorigenesis. Nat Rev Cancer 6(3):184–192PubMedCrossRefPubMedCentralGoogle Scholar
  65. 65.
    Hietakangas V, Cohen SM (2009) Regulation of tissue growth through nutrient sensing. Annu Rev Genet 43:389–410PubMedCrossRefPubMedCentralGoogle Scholar
  66. 66.
    Oldham S, Hafen E (2003) Insulin/IGF and target of rapamycin signaling: a TOR de force in growth control. Trends Cell Biol 13(2):79–85PubMedCrossRefPubMedCentralGoogle Scholar
  67. 67.
    Teleman AA (2009) Molecular mechanisms of metabolic regulation by insulin in Drosophila. Biochem J 425(1):13–26PubMedCrossRefPubMedCentralGoogle Scholar
  68. 68.
    Herranz H, Cohen SM (2017) Drosophila as a model to study the link between metabolism and cancer. J Dev Biol:5(4)PubMedCentralCrossRefGoogle Scholar
  69. 69.
    Basu S (2011) PP2A in the regulation of cell motility and invasion. Curr Protein Pept Sci 12(1):3–11PubMedCrossRefPubMedCentralGoogle Scholar
  70. 70.
    Janssens V, Goris J (2001) Protein phosphatase 2A: a highly regulated family of serine/threonine phosphatases implicated in cell growth and signalling. Biochem J 353(Pt 3):417–439PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Chen F et al (2007) Multiple protein phosphatases are required for mitosis in Drosophila. Curr Biol 17(4):293–303PubMedCrossRefPubMedCentralGoogle Scholar
  72. 72.
    Deak P, Donaldson M, Glover DM (2003) Mutations in makos, a Drosophila gene encoding the Cdc27 subunit of the anaphase promoting complex, enhance centrosomal defects in polo and are suppressed by mutations in twins/aar, which encodes a regulatory subunit of PP2A. J Cell Sci 116(Pt 20):4147–4158PubMedCrossRefPubMedCentralGoogle Scholar
  73. 73.
    Wang C et al (2009) Protein phosphatase 2A regulates self-renewal of Drosophila neural stem cells. Development 136(13):2287–2296PubMedCrossRefPubMedCentralGoogle Scholar
  74. 74.
    Banreti A et al (2012) PP2A regulates autophagy in two alternative ways in Drosophila. Autophagy 8(4):623–636PubMedCrossRefPubMedCentralGoogle Scholar
  75. 75.
    Fischer P, Preiss A, Nagel AC (2016) A triangular connection between cyclin G, PP2A and Akt1 in the regulation of growth and metabolism in Drosophila. Fly (Austin) 10(1):11–18CrossRefGoogle Scholar
  76. 76.
    Miller JR (2002) The Wnts. Genome Biol 3(1):REVIEWS3001PubMedPubMedCentralGoogle Scholar
  77. 77.
    Tian A et al (2017) Intestinal stem cell overproliferation resulting from inactivation of the APC tumor suppressor requires the transcription cofactors earthbound and erect wing. PLoS Genet 13(7):e1006870PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Mittag S et al (2016) A novel role for the tumour suppressor Nitrilase1 modulating the Wnt/beta-catenin signalling pathway. Cell Discov 2:15039PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Kunttas-Tatli E, Roberts DM, McCartney BM (2014) Self-association of the APC tumor suppressor is required for the assembly, stability, and activity of the Wnt signaling destruction complex. Mol Biol Cell 25(21):3424–3436PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Swarup S, Verheyen EM (2012) Wnt/Wingless signaling in Drosophila. Cold Spring Harb Perspect Biol:4(6)PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Alexandre C, Baena-Lopez A, Vincent JP (2014) Patterning and growth control by membrane-tethered wingless. Nature 505(7482):180–185PubMedCrossRefPubMedCentralGoogle Scholar
  82. 82.
    Yamashita YM, Jones DL, Fuller MT (2003) Orientation of asymmetric stem cell division by the APC tumor suppressor and centrosome. Science 301(5639):1547–1550PubMedCrossRefPubMedCentralGoogle Scholar
  83. 83.
    Roberts DM et al (2012) Regulation of Wnt signaling by the tumor suppressor adenomatous polyposis coli does not require the ability to enter the nucleus or a particular cytoplasmic localization. Mol Biol Cell 23(11):2041–2056PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Cordero J, Vidal M, Sansom O (2009) APC as a master regulator of intestinal homeostasis and transformation: from flies to vertebrates. Cell Cycle 8(18):2926–2931PubMedCrossRefPubMedCentralGoogle Scholar
  85. 85.
    Cordero JB et al (2012) Inducible progenitor-derived wingless regulates adult midgut regeneration in Drosophila. EMBO J 31(19):3901–3917PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Lee WC et al (2009) Adenomatous polyposis coli regulates Drosophila intestinal stem cell proliferation. Development 136(13):2255–2264PubMedCrossRefPubMedCentralGoogle Scholar
  87. 87.
    Ingham PW (2018) From Drosophila segmentation to human cancer therapy. Development 145(21)PubMedCrossRefPubMedCentralGoogle Scholar
  88. 88.
    Song W et al (2017) Midgut-derived Activin regulates glucagon-like action in the fat body and glycemic control. Cell Metab 25(2):386–399PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Garelli A et al (2012) Imaginal discs secrete insulin-like peptide 8 to mediate plasticity of growth and maturation. Science 336(6081):579–582PubMedCrossRefPubMedCentralGoogle Scholar
  90. 90.
    Colombani J, Andersen DS, Leopold P (2012) Secreted peptide Dilp8 coordinates Drosophila tissue growth with developmental timing. Science 336(6081):582–585PubMedCrossRefPubMedCentralGoogle Scholar
  91. 91.
    Thorsson V et al (2018) The immune landscape of Cancer. Immunity 48(4):812–830. e14PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Vaure C, Liu Y (2014) A comparative review of toll-like receptor 4 expression and functionality in different animal species. Front Immunol 5:316PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Imler JL et al (2004) Toll-dependent and toll-independent immune responses in Drosophila. J Endotoxin Res 10(4):241–246PubMedCrossRefPubMedCentralGoogle Scholar
  94. 94.
    Kadoch C et al (2013) Proteomic and bioinformatic analysis of mammalian SWI/SNF complexes identifies extensive roles in human malignancy. Nat Genet 45(6):592–601PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Yaniv M (2014) Chromatin remodeling: from transcription to cancer. Cancer Genet 207(9):352–357PubMedCrossRefPubMedCentralGoogle Scholar
  96. 96.
    Dingwall AK et al (1995) The Drosophila snr1 and brm proteins are related to yeast SWI/SNF proteins and are components of a large protein complex. Mol Biol Cell 6(7):777–791PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Stern M, Jensen R, Herskowitz I (1984) Five SWI genes are required for expression of the HO gene in yeast. J Mol Biol 178(4):853–868PubMedCrossRefPubMedCentralGoogle Scholar
  98. 98.
    Ho L et al (2009) An embryonic stem cell chromatin remodeling complex, esBAF, is essential for embryonic stem cell self-renewal and pluripotency. Proc Natl Acad Sci U S A 106(13):5181–5186PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Mashtalir N et al (2018) Modular organization and assembly of SWI/SNF family chromatin remodeling complexes. Cell 175(5):1272–1288. e20PubMedCrossRefPubMedCentralGoogle Scholar
  100. 100.
    Eroglu E et al (2014) SWI/SNF complex prevents lineage reversion and induces temporal patterning in neural stem cells. Cell 156(6):1259–1273PubMedCrossRefPubMedCentralGoogle Scholar
  101. 101.
    Bonnay F et al (2014) Akirin specifies NF-kappaB selectivity of Drosophila innate immune response via chromatin remodeling. EMBO J 33(20):2349–2362PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Pandey UB, Nichols CD (2011) Human disease models in Drosophila melanogaster and the role of the fly in therapeutic drug discovery. Pharmacol Rev 63(2):411–436PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Reiter LT et al (2001) A systematic analysis of human disease-associated gene sequences in Drosophila melanogaster. Genome Res 11(6):1114–1125PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Levinson S, Cagan RL (2016) Drosophila Cancer models identify functional differences between ret fusions. Cell Rep 16(11):3052–3061PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Salomon RN, Jackson FR (2008) Tumors of testis and midgut in aging flies. Fly (Austin) 2(6):265–268CrossRefGoogle Scholar
  106. 106.
    Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674CrossRefGoogle Scholar
  107. 107.
    Bokel C (2008) EMS screens : from mutagenesis to screening and mapping. Methods Mol Biol 420:119–138PubMedCrossRefPubMedCentralGoogle Scholar
  108. 108.
    Justice RW et al (1995) The Drosophila tumor suppressor gene warts encodes a homolog of human myotonic dystrophy kinase and is required for the control of cell shape and proliferation. Genes Dev 9(5):534–546PubMedCrossRefPubMedCentralGoogle Scholar
  109. 109.
    Xu T et al (1995) Identifying tumor suppressors in genetic mosaics: the Drosophila lats gene encodes a putative protein kinase. Development 121(4):1053–1063PubMedPubMedCentralGoogle Scholar
  110. 110.
    Harvey K, Tapon N (2007) The Salvador-warts-Hippo pathway – an emerging tumour-suppressor network. Nat Rev Cancer 7(3):182–191PubMedCrossRefPubMedCentralGoogle Scholar
  111. 111.
    Nusslein-Volhard C, Wieschaus E (1980) Mutations affecting segment number and polarity in Drosophila. Nature 287(5785):795–801PubMedCrossRefPubMedCentralGoogle Scholar
  112. 112.
    Rubin GM, Spradling AC (1982) Genetic transformation of Drosophila with transposable element vectors. Science 218(4570):348–353PubMedCrossRefPubMedCentralGoogle Scholar
  113. 113.
    Spradling AC, Rubin GM (1982) Transposition of cloned P elements into Drosophila germ line chromosomes. Science 218(4570):341–347PubMedCrossRefPubMedCentralGoogle Scholar
  114. 114.
    Thibault ST et al (2004) A complementary transposon tool kit for Drosophila melanogaster using P and piggyBac. Nat Genet 36(3):283–287PubMedCrossRefPubMedCentralGoogle Scholar
  115. 115.
    Spradling AC et al (1999) The Berkeley Drosophila genome project gene disruption project: single P-element insertions mutating 25% of vital Drosophila genes. Genetics 153(1):135–177PubMedPubMedCentralGoogle Scholar
  116. 116.
    Bellen HJ et al (2011) The Drosophila gene disruption project: progress using transposons with distinctive site specificities. Genetics 188(3):731–743PubMedPubMedCentralCrossRefGoogle Scholar
  117. 117.
    Parks AL et al (2004) Systematic generation of high-resolution deletion coverage of the Drosophila melanogaster genome. Nat Genet 36(3):288–292PubMedCrossRefPubMedCentralGoogle Scholar
  118. 118.
    Venken KJ et al (2011) MiMIC: a highly versatile transposon insertion resource for engineering Drosophila melanogaster genes. Nat Methods 8(9):737–743PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Brand AH, Perrimon N (1993) Targeted gene expression as a means of altering cell fates and generating dominant phenotypes. Development 118(2):401–415PubMedGoogle Scholar
  120. 120.
    Kvon EZ et al (2014) Genome-scale functional characterization of Drosophila developmental enhancers in vivo. Nature 512(7512):91–95PubMedCrossRefPubMedCentralGoogle Scholar
  121. 121.
    Jenett A et al (2012) A GAL4-driver line resource for Drosophila neurobiology. Cell Rep 2(4):991–1001PubMedPubMedCentralCrossRefGoogle Scholar
  122. 122.
    Toba G et al (1999) The gene search system. A method for efficient detection and rapid molecular identification of genes in Drosophila melanogaster. Genetics 151(2):725–737PubMedPubMedCentralGoogle Scholar
  123. 123.
    Ferres-Marco D et al (2006) Epigenetic silencers and notch collaborate to promote malignant tumours by Rb silencing. Nature 439(7075):430–436CrossRefGoogle Scholar
  124. 124.
    Palomero T et al (2007) Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia. Nat Med 13(10):1203–1210PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Rorth P (1996) A modular misexpression screen in Drosophila detecting tissue-specific phenotypes. Proc Natl Acad Sci U S A 93(22):12418–12422PubMedPubMedCentralCrossRefGoogle Scholar
  126. 126.
    Huang AM, Rubin GM (2000) A misexpression screen identifies genes that can modulate RAS1 pathway signaling in Drosophila melanogaster. Genetics 156(3):1219–1230PubMedPubMedCentralGoogle Scholar
  127. 127.
    Fire A et al (1998) Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 391(6669):806–811PubMedCrossRefPubMedCentralGoogle Scholar
  128. 128.
    Bischof J et al (2013) A versatile platform for creating a comprehensive UAS-ORFeome library in Drosophila. Development 140(11):2434–2442PubMedCrossRefPubMedCentralGoogle Scholar
  129. 129.
    Dietzl G et al (2007) A genome-wide transgenic RNAi library for conditional gene inactivation in Drosophila. Nature 448(7150):151–156PubMedCrossRefPubMedCentralGoogle Scholar
  130. 130.
    Housden BE et al (2017) Loss-of-function genetic tools for animal models: cross-species and cross-platform differences. Nat Rev Genet 18(1):24–40PubMedCrossRefPubMedCentralGoogle Scholar
  131. 131.
    Muller P et al (2005) Identification of JAK/STAT signalling components by genome-wide RNA interference. Nature 436(7052):871–875PubMedCrossRefPubMedCentralGoogle Scholar
  132. 132.
    Bier E et al (2018) Advances in engineering the fly genome with the CRISPR-Cas system. Genetics 208(1):1–18PubMedCrossRefGoogle Scholar
  133. 133.
    Gratz SJ et al (2014) Highly specific and efficient CRISPR/Cas9-catalyzed homology-directed repair in Drosophila. Genetics 196(4):961–971PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Port F et al (2014) Optimized CRISPR/Cas tools for efficient germline and somatic genome engineering in Drosophila. Proc Natl Acad Sci U S A 111(29):E2967–E2976PubMedPubMedCentralCrossRefGoogle Scholar
  135. 135.
    Millburn GH, Crosby MA, Gramates LS, Tweedie S, the FlyBase Consortium (2016) FlyBase portals to human disease research using Drosophila models. Dis Model Mech 9(3):245–252Google Scholar
  136. 136.
    Garcia-Bellido A, Dapena J (1974) Induction, detection and characterization of cell differentiation mutants in Drosophila. Mol Gen Genet 128(2):117–130PubMedCrossRefPubMedCentralGoogle Scholar
  137. 137.
    Golic KG, Lindquist S (1989) The FLP recombinase of yeast catalyzes site-specific recombination in the Drosophila genome. Cell 59(3):499–509PubMedCrossRefPubMedCentralGoogle Scholar
  138. 138.
    Xu T, Rubin GM (1993) Analysis of genetic mosaics in developing and adult Drosophila tissues. Development 117(4):1223–1237PubMedGoogle Scholar
  139. 139.
    Golic KG (1991) Site-specific recombination between homologous chromosomes in Drosophila. Science 252(5008):958–961PubMedCrossRefPubMedCentralGoogle Scholar
  140. 140.
    Lee T, Luo L (1999) Mosaic analysis with a repressible cell marker for studies of gene function in neuronal morphogenesis. Neuron 22(3):451–461PubMedCrossRefPubMedCentralGoogle Scholar
  141. 141.
    Wu JS, Luo L (2006) A protocol for mosaic analysis with a repressible cell marker (MARCM) in Drosophila. Nat Protoc 1(6):2583–2589PubMedCrossRefPubMedCentralGoogle Scholar
  142. 142.
    Hadjieconomou D et al (2011) Flybow: genetic multicolor cell labeling for neural circuit analysis in Drosophila melanogaster. Nat Methods 8(3):260–266PubMedCrossRefPubMedCentralGoogle Scholar
  143. 143.
    Potter CJ et al (2010) The Q system: a repressible binary system for transgene expression, lineage tracing, and mosaic analysis. Cell 141(3):536–548PubMedPubMedCentralCrossRefGoogle Scholar
  144. 144.
    Yagi R, Mayer F, Basler K (2010) Refined LexA transactivators and their use in combination with the Drosophila Gal4 system. Proc Natl Acad Sci U S A 107(37):16166–16171PubMedPubMedCentralCrossRefGoogle Scholar
  145. 145.
    Bosch JA, Tran NH, Hariharan IK (2015) CoinFLP: a system for efficient mosaic screening and for visualizing clonal boundaries in Drosophila. Development 142(3):597–606PubMedPubMedCentralCrossRefGoogle Scholar
  146. 146.
    Gateff E (1978) Malignant neoplasms of genetic origin in Drosophila melanogaster. Science 200(4349):1448–1459PubMedCrossRefGoogle Scholar
  147. 147.
    Rossi F, Gonzalez C (2015) Studying tumor growth in Drosophila using the tissue allograft method. Nat Protoc 10(10):1525–1534PubMedCrossRefGoogle Scholar
  148. 148.
    Gladstone M, Su TT (2011) Chemical genetics and drug screening in Drosophila cancer models. J Genet Genomics 38(10):497–504PubMedCrossRefGoogle Scholar
  149. 149.
    Dar AC, Das TK, Shokat KM, Cagan RL (2012) Chemical genetic discovery of targets and anti-targets for cancer polypharmacology. Nature 486:80–84PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Instituto de Neurociencias, Consejo Superior de Investigaciones Cientificas (CSIC) and Universidad Miguel Hernández (UMH)AlicanteSpain

Personalised recommendations