What Drosophila Can Teach Us About Radiation Biology of Human Cancers

  • Tin Tin SuEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1167)


Ionizing radiation (IR) is used to treat more than half of human cancer patients. The therapeutic effect of IR is due to its ability to induce apoptosis. Success of radiation therapy relies not only on apoptosis induction but also on whether surviving cancer cells proliferate and regenerate a tumor. Drosophila melanogaster is a premier genetic model and, relevant to radiation biology of cancer, Drosophila larvae display an amazing capacity to regenerate. IR doses that kill more than half of the cells in larval tissues still allow complete regeneration to produce an adult fly of normal size and pattern. It is by understanding not only the initial effects of IR such as DNA damage and cell death but also longer-term regenerative responses that we may manipulate and improve radiation therapy of cancer. In this regard, Drosophila offers an unparalleled model to study both types of responses.


Drosophila Cancer Ionizing radiation Apoptosis Regeneration 



Apoptosis-induced Proliferation

F1 and F2

Filial 1, Filial 2


Ionizing Radiation


Janus kinase


c-Jun N-terminal Kinase


Prostaglandin E2


Reactive Oxygen Species


Signal Transducer and Activator of Transcription



TTS is supported by an NIH grant, R35 GM130374. The author thanks Corrie Detweiler and Barbara Frederick for critical reading of the manuscript.

Conflict of Interest

The author owns equity in SuviCa, Inc.


  1. 1.
    Bilak A, Uyetake L, Su TT (2014) Dying cells protect survivors from radiation-induced cell death in Drosophila. PLoS Genet 10:e1004220CrossRefGoogle Scholar
  2. 2.
    Brock AR, Seto M, Smith-Bolton RK (2017) Cap-n-collar promotes tissue regeneration by regulating ROS and JNK Signaling in the Drosophila melanogaster wing imaginal disc. Genetics 206:1505–1520CrossRefGoogle Scholar
  3. 3.
    Carlson EA (2009) Herman Joseph Muller. In: Biographical Memoirs; volume 91. National Academies Press, Washington, DCGoogle Scholar
  4. 4.
    Clark AM (1956) Genetic effects of x-rays in relation to dose-rate in Drosophila. Nature 177:787CrossRefGoogle Scholar
  5. 5.
    Debeb BG, Lacerda L, Xu W, Larson R, Solley T, Atkinson R, Sulman EP, Ueno NT, Krishnamurthy S, Reuben JM, Buchholz TA, Woodward WA (2012) Histone deacetylase inhibitors stimulate dedifferentiation of human breast cancer cells through WNT/beta-catenin signaling. Stem Cells 30:2366–2377CrossRefGoogle Scholar
  6. 6.
    Fan Y, Bergmann A (2008a) Apoptosis-induced compensatory proliferation. The cell is dead. Long live the cell! Trends Cell Biol 18:467–473CrossRefGoogle Scholar
  7. 7.
    Fan Y, Bergmann A (2008b) Distinct mechanisms of apoptosis-induced compensatory proliferation in proliferating and differentiating tissues in the Drosophila eye. Dev Cell 14:399–410CrossRefGoogle Scholar
  8. 8.
    Fan Y, Wang S, Hernandez J, Yenigun VB, Hertlein G, Fogarty CE, Lindblad JL, Bergmann A (2014) Genetic models of apoptosis-induced proliferation decipher activation of JNK and identify a requirement of EGFR signaling for tissue regenerative responses in Drosophila. PLoS Genet 10:e1004131CrossRefGoogle Scholar
  9. 9.
    Fogarty CE, Bergmann A (2015) The sound of silence: signaling by apoptotic cells. Curr Top Dev Biol 114:241–265CrossRefGoogle Scholar
  10. 10.
    Fogarty CE, Diwanji N, Lindblad JL, Tare M, Amcheslavsky A, Makhijani K, Bruckner K, Fan Y, Bergmann A (2016) Extracellular reactive oxygen species drive apoptosis-induced proliferation via Drosophila macrophages. Curr Biol 26:575–584CrossRefGoogle Scholar
  11. 11.
    Gladstone M, Frederick B, Zheng D, Edwards A, Yoon P, Stickel S, Delaney T, Chan DC, Raben D, Su TT (2012) A translation inhibitor identified in a Drosophila screen enhances the effect of ionizing radiation and taxol in mammalian models of cancer. Dis Model Mech 5:342–350CrossRefGoogle Scholar
  12. 12.
    Gladstone M, Su TT (2011a) Chemical genetics and drug screening in Drosophila cancer models. J Genet Genomics 38:497–504CrossRefGoogle Scholar
  13. 13.
    Gladstone M, Su TT (2011b) Screening for radiation sensitizers of Drosophila checkpoint mutants. Methods Mol Biol 782:105–117CrossRefGoogle Scholar
  14. 14.
    Grompe M (2014) Liver stem cells, where art thou? Cell Stem Cell 15:257–258CrossRefGoogle Scholar
  15. 15.
    Hall E, Giaccia AJ (2006) Radiobiology for the radiologist. Lippincott Williams & Wilkins, PhiladelphiaGoogle Scholar
  16. 16.
    Halme A, Cheng M, Hariharan IK (2010) Retinoids regulate a developmental checkpoint for tissue regeneration in Drosophila. Curr Biol 20:458–463CrossRefGoogle Scholar
  17. 17.
    Haynie JL, Bryant PJ (1977) The effects of X-rays on the proliferation dynamics of cells in the imaginal wing disc of Drosophila melanogaster. Wilhelm Roux’s archives of developmental biology 183:85–100CrossRefGoogle Scholar
  18. 18.
    Hinton CW, Whittinghill M (1950) The distribution of x-ray induced crossovers from Curly inversion heterozygotes of drosophila melanogaster females. Proc Natl Acad Sci U S A 36:552–558CrossRefGoogle Scholar
  19. 19.
    Huang Q, Li F, Liu X, Li W, Shi W, Liu FF, O’sullivan B, He Z, Peng Y, Tan AC, Zhou L, Shen J, Han G, Wang XJ, Thorburn J, Thorburn A, Jimeno A, Raben D, Bedford JS, Li CY (2011) Caspase 3-mediated stimulation of tumor cell repopulation during cancer radiotherapy. Nat Med 17:860–866CrossRefGoogle Scholar
  20. 20.
    Jaklevic B, Uyetake L, Lemstra W, Chang J, Leary W, Edwards A, Vidwans S, Sibon O, Tin Su T (2006) Contribution of growth and cell cycle checkpoints to radiation survival in Drosophila. Genetics 174:1963–1972CrossRefGoogle Scholar
  21. 21.
    Jaklevic BR, Su TT (2004) Relative contribution of DNA repair, cell cycle checkpoints, and cell death to survival after DNA damage in Drosophila larvae. Curr Biol 14:23–32CrossRefGoogle Scholar
  22. 22.
    James AA, Bryant PJ (1981) A quantitative study of cell death and mitotic inhibition in gamma-irradiated imaginal wing discs of Drosophila melanogaster. Radiat Res 87:552–564CrossRefGoogle Scholar
  23. 23.
    Karpen GH, Schubiger G (1981) Extensive regulatory capabilities of a Drosophila imaginal disk blastema. Nature 294:744–747CrossRefGoogle Scholar
  24. 24.
    Kaufman TC (2017) A short history and description of Drosophila melanogaster classical genetics: chromosome aberrations, forward genetic screens, and the nature of mutations. Genetics 206:665–689CrossRefGoogle Scholar
  25. 25.
    Kelsey EM, Luo X, Bruckner K, Jasper H (2012) Schnurri regulates hemocyte function to promote tissue recovery after DNA damage. J Cell Sci 125:1393–1400CrossRefGoogle Scholar
  26. 26.
    Keysar SB, Le PN, Miller B, Jackson BC, Eagles JR, Nieto C, Kim J, Tang B, Glogowska MJ, Morton JJ, Padilla-Just N, Gomez K, Warnock E, Reisinger J, Arcaroli JJ, Messersmith WA, Wakefield LM, Gao D, Tan AC, Serracino H, Vasiliou V, Roop DR, Wang XJ, Jimeno A (2017) Regulation of head and neck squamous cancer stem cells by PI3K and SOX2. J Natl Cancer Inst 109:1–12CrossRefGoogle Scholar
  27. 27.
    Khan SJ, Abidi SNF, Skinner A, Tian Y, Smith-Bolton RK (2017) The Drosophila Duox maturation factor is a key component of a positive feedback loop that sustains regeneration signaling. PLoS Genet 13:e1006937CrossRefGoogle Scholar
  28. 28.
    Kondo S, Senoo-Matsuda N, Hiromi Y, Miura M (2006) DRONC coordinates cell death and compensatory proliferation. Mol Cell Biol 26:7258–7268CrossRefGoogle Scholar
  29. 29.
    Kruiswijk F, Yuniati L, Magliozzi R, Low TY, Lim R, Bolder R, Mohammed S, Proud CG, Heck AJ, Pagano M, Guardavaccaro D (2012) Coupled activation and degradation of eEF2K regulates protein synthesis in response to genotoxic stress. Sci Signal 5:ra40CrossRefGoogle Scholar
  30. 30.
    Lagadec C, Vlashi E, Della Donna L, Dekmezian C, Pajonk F (2012) Radiation-induced reprogramming of breast cancer cells. Stem Cells 30:833–844CrossRefGoogle Scholar
  31. 31.
    Larocque JR, Jaklevic B, Su TT, Sekelsky J (2007) Drosophila ATR in double-strand break repair. Genetics 175:1023–1033CrossRefGoogle Scholar
  32. 32.
    Lee SY, Jeong EK, Ju MK, Jeon HM, Kim MY, Kim CH, Park HG, Han SI, Kang HS (2017) Induction of metastasis, cancer stem cell phenotype, and oncogenic metabolism in cancer cells by ionizing radiation. Mol Cancer 16:10CrossRefGoogle Scholar
  33. 33.
    Li F, Huang Q, Chen J, Peng Y, Roop DR, Bedford JS, Li CY (2010) Apoptotic cells activate the “phoenix rising” pathway to promote wound healing and tissue regeneration. Sci Signal 3:ra13PubMedPubMedCentralGoogle Scholar
  34. 34.
    Ma J, Tian L, Cheng J, Chen Z, Xu B, Wang L, Li C, Huang Q (2013) Sonic hedgehog signaling pathway supports cancer cell growth during cancer radiotherapy. PLoS One 8:e65032CrossRefGoogle Scholar
  35. 35.
    Marjanovic ND, Weinberg RA, Chaffer CL (2013) Cell plasticity and heterogeneity in cancer. Clin Chem 59:168–179CrossRefGoogle Scholar
  36. 36.
    Michalopoulos GK (2007) Liver regeneration. J Cell Physiol 213:286–300CrossRefGoogle Scholar
  37. 37.
    Michalopoulos GK, Khan Z (2015) Liver stem cells: experimental findings and implications for human liver disease. Gastroenterology 149:876–882CrossRefGoogle Scholar
  38. 38.
    Mollereau B, Perez-Garijo A, Bergmann A, Miura M, Gerlitz O, Ryoo HD, Steller H, Morata G (2013) Compensatory proliferation and apoptosis-induced proliferation: a need for clarification. Cell Death Differ 20:181CrossRefGoogle Scholar
  39. 39.
    Muller HJ (1927) Artificial transmutation of the gene. Science 66:84–87CrossRefGoogle Scholar
  40. 40.
    Muller HJ (1928) The production of mutations by X-rays. Proc Natl Acad Sci U S A 14:714–726CrossRefGoogle Scholar
  41. 41.
    Muller HJ, Altenburg E (1930) The frequency of translocations produced by X-rays in Drosophila. Genetics 15:283–311PubMedPubMedCentralGoogle Scholar
  42. 42.
    Muller HJ, Kaplan WD (1966) The dosage compensation of Drosophila and mammals as showing the accuracy of the normal type. Genet Res 8:41–59CrossRefGoogle Scholar
  43. 43.
    Perez E, Lindblad JL, Bergmann A (2017, Aug 30) Tumor-promoting function of apoptotic caspases by an amplification loop involving ROS, macrophages and JNK in Drosophila. elife 6:e26747Google Scholar
  44. 44.
    Perez-Garijo A, Shlevkov E, Morata G (2009) The role of Dpp and Wg in compensatory proliferation and in the formation of hyperplastic overgrowths caused by apoptotic cells in the Drosophila wing disc. Development 136:1169–1177CrossRefGoogle Scholar
  45. 45.
    Pisco AO, Huang S (2015) Non-genetic cancer cell plasticity and therapy-induced stemness in tumour relapse: ‘What does not kill me strengthens me’. Br J Cancer 112:1725–1732CrossRefGoogle Scholar
  46. 46.
    Postlethwait JH, Schneiderman HA (1973) Pattern formation in imaginal discs of Drosophila melanogaster after irradiation of embryos and young larvae. Dev Biol 32:345–360CrossRefGoogle Scholar
  47. 47.
    Quintana E, Shackleton M, Sabel MS, Fullen DR, Johnson TM, Morrison SJ (2008) Efficient tumour formation by single human melanoma cells. Nature 456:593–598CrossRefGoogle Scholar
  48. 48.
    Raffel D, Muller HJ (1940) Position effect and gene divisibility considered in connection with three strikingly similar Scute mutations. Genetics 25:541–583PubMedPubMedCentralGoogle Scholar
  49. 49.
    Ray-Chaudhuri SP (1944) IX.—the validity of the Bunsen-roscoe law in the production of mutations by radiation of extremely low intensity. Proceedings of the Royal Society of Edinburgh, Section B: Biological Sciences 62:66–72CrossRefGoogle Scholar
  50. 50.
    Rugo RE, Secretan MB, Schiestl RH (2002) X radiation causes a persistent induction of reactive oxygen species and a delayed reinduction of TP53 in normal human diploid fibroblasts. Radiat Res 158:210–219CrossRefGoogle Scholar
  51. 51.
    Ryoo HD, Bergmann A (2012) The role of apoptosis-induced proliferation for regeneration and cancer. Cold Spring Harb Perspect Biol 4:a008797CrossRefGoogle Scholar
  52. 52.
    Schubiger G (1971) Regeneration, duplication and transdetermination in fragments of the leg disc of Drosophila melanogaster. Dev Biol 26:277–295CrossRefGoogle Scholar
  53. 53.
    Schuster KJ, Smith-Bolton RK (2015) Taranis protects regenerating tissue from fate changes induced by the wound response in Drosophila. Dev Cell 34:119–128CrossRefGoogle Scholar
  54. 54.
    Skinner A, Khan SJ, Smith-Bolton RK (2015) Trithorax regulates systemic signaling during Drosophila imaginal disc regeneration. Development 142:3500–3511CrossRefGoogle Scholar
  55. 55.
    Smith-Bolton RK, Worley MI, Kanda H, Hariharan IK (2009) Regenerative growth in Drosophila imaginal discs is regulated by Wingless and Myc. Dev Cell 16:797–809CrossRefGoogle Scholar
  56. 56.
    Sobels FH (1960) Chemical steps involved in the production of mutations and chromosome aberrations by x-irradiation in Drosophila. I. The effect of post-treatment with cyanide in relation to dose-rate and oxygen tension. Int J Radiat Biol Relat Stud Phys Chem Med 2:68–90CrossRefGoogle Scholar
  57. 57.
    Stickel SA, Gomes NP, Frederick B, Raben D, Su TT (2015) Bouvardin is a radiation modulator with a novel mechanism of action. Radiat Res 184:392–403CrossRefGoogle Scholar
  58. 58.
    Strehler BL (1964) Studies on the comparative physiology of aging. Iii. Effects of X-radiation dosage on age-specific mortality rates of Drosophila melanogaster and Campanularia Flexuosa. J Gerontol 19:83–87CrossRefGoogle Scholar
  59. 59.
    Sun Y, Campisi J, Higano C, Beer TM, Porter P, Coleman I, True L, Nelson PS (2012) Treatment-induced damage to the tumor microenvironment promotes prostate cancer therapy resistance through WNT16B. Nat Med 18:1359–1368CrossRefGoogle Scholar
  60. 60.
    Van Bergeijk P, Heimiller J, Uyetake L, Su TT (2012) Genome-wide expression analysis identifies a modulator of ionizing radiation-induced p53-independent apoptosis in Drosophila melanogaster. PLoS One 7:e36539CrossRefGoogle Scholar
  61. 61.
    Verghese S, Su TT (2016) Drosophila Wnt and STAT define apoptosis-resistant epithelial cells for tissue regeneration after irradiation. PLoS Biol 14:e1002536CrossRefGoogle Scholar
  62. 62.
    Verghese S, Su TT (2017) STAT, Wingless, and Nurf-38 determine the accuracy of regeneration after radiation damage in Drosophila. PLoS Genet 13:e1007055CrossRefGoogle Scholar
  63. 63.
    Verghese S, Su TT (2018) Ionizing radiation induces stem cell-like properties in a caspase-dependent manner in Drosophila. PLoS Genet 21:2018Google Scholar
  64. 64.
    Villee CA (1946) Some effects of x-rays on development in Drosophila. J Exp Zool 101:261–280CrossRefGoogle Scholar
  65. 65.
    Vlashi E, Chen AM, Boyrie S, Yu G, Nguyen A, Brower PA, Hess CB, Pajonk F (2016) Radiation-induced dedifferentiation of head and neck cancer cells into cancer stem cells depends on human papillomavirus status. Int J Radiat Oncol Biol Phys 94:1198–1206CrossRefGoogle Scholar
  66. 66.
    Weber W, Zanzonico P (2017) The controversial linear no-threshold model. J Nucl Med 58:7–8CrossRefGoogle Scholar
  67. 67.
    Weichselbaum RR, Liang H, Deng L, Fu YX (2017) Radiotherapy and immunotherapy: a beneficial liaison? Nat Rev Clin Oncol 14:365–379CrossRefGoogle Scholar
  68. 68.
    Wells BS, Johnston LA (2012) Maintenance of imaginal disc plasticity and regenerative potential in Drosophila by p53. Dev Biol 361:263–276CrossRefGoogle Scholar
  69. 69.
    Worley MI, Setiawan L, Hariharan IK (2012) Regeneration and transdetermination in Drosophila imaginal discs. Annu Rev Genet 46:289–310CrossRefGoogle Scholar
  70. 70.
    Xu HS, Qin XL, Zong HL, He XG, Cao L (2017) Cancer stem cell markers in glioblastoma – an update. Eur Rev Med Pharmacol Sci 21:3207–3211PubMedGoogle Scholar
  71. 71.
    Ye X, Weinberg RA (2015) Epithelial-mesenchymal plasticity: a central regulator of cancer progression. Trends Cell Biol 25:675–686CrossRefGoogle Scholar

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Authors and Affiliations

  1. 1.Department of Molecular, Cellular, and Developmental Biology 347 UCBUniversity of ColoradoBoulderUSA
  2. 2.University of Colorado Comprehensive Cancer CenterAuroraUSA

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