Drosophila melanogaster: A model and a tool to investigate malignancy and identify new therapeutics

Nature Reviews Cancer

Volumn 13, Issue 3, 2013, Pages 172-183

  Gonzalez, Cayetano ^a,b  

^a INSTITUTE FOR RESEARCH IN BIOMEDICINE   (Spain)

^b INSTITUCIÓ CATALANA DE RECERCA I ESTUDIS AVANÇATS ICREA   (Spain)

Author keywords

[No Author keywords available]

Indexed keywords

ANAPLASTIC LYMPHOMA KINASE; AURORA A KINASE; BETA CATENIN; BONE MORPHOGENETIC PROTEIN 2; CALPAIN B; CELL DIVISION CYCLE 16; CO REPRESSOR FOR ELEMENT 1 SILENCING TRANSCRIPTION FACTOR; GLYCOGEN SYNTHASE KINASE 3BETA; JANUS KINASE; MITOGEN ACTIVATED PROTEIN KINASE 10; PHOSPHATIDYLINOSITOL 3,4,5 TRISPHOSPHATE 3 PHOSPHATASE; POLO LIKE KINASE; POLYCOMB GROUP PROTEIN; PROTEIN KINASE C; PROTEIN P53; PROTEINASE; STAT PROTEIN; TRANSCRIPTION FACTOR; TRANSCRIPTION FACTOR FKHR; UNCLASSIFIED DRUG; WNT PROTEIN;

ANEUPLOIDY; CELL POLARITY; DROSOPHILA MELANOGASTER; GENOMIC INSTABILITY; HUMAN; MUTAGENESIS; NEOPLASM; NONHUMAN; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN FUNCTION; REVIEW; SIGNAL TRANSDUCTION; STOMACH ADENOCARCINOMA;

ANIMALS; DISEASE MODELS, ANIMAL; DROSOPHILA MELANOGASTER; DRUG DISCOVERY; HUMANS; NEOPLASMS;

EID: 84875412051     PISSN: 1474175X     EISSN: 14741768     Source Type: Journal    
DOI: 10.1038/nrc3461     Document Type: Review

References (168)

1. Adams, M. D. et al. The genome sequence of Drosophila melanogaster. Science 287, 2185-2195 (2000).
2. Rubin, G. M. et al. Comparative genomics of the eukaryotes. Science 287, 2204-2215 (2000).
3. Brumby, A. M. & Richardson, H. E. Using Drosophila melanogaster to map human cancer pathways. Nature Rev. Cancer 5, 626-639 (2005).
4. Ellisen, L. W. et al. TAN-1, the human homolog of the Drosophila notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms. Cell 66, 649-661 (1991).
5. Ranganathan, P., Weaver, K. L. & Capobianco, A. J. Notch signalling in solid tumours: a little bit of everything but not all the time. Nature Rev. Cancer 11, 338-351 (2011).
6. Pancewicz, J. & Nicot, C. Current views on the role of Notch signaling and the pathogenesis of human leukemia. BMC Cancer 1166, 502 (2011).
7. Purow, B. Notch inhibitors as a new tool in the war on cancer: a pathway to watch. Curr. Pharm. Biotechnol. 10, 154-160 (2009).
8. Barakat, M. T., Humke, E. W. & Scott, M. P. Learning from Jekyll to control Hyde: Hedgehog signaling in development and cancer. Trends Mol. Med. 16, 337-348 (2010).
9. Harvey, K. & Tapon, N. The Salvador-Warts-Hippo pathway - an emerging tumour-suppressor network. Nature Rev. Cancer 7, 182-191 (2007).
10. Staley, B. K. & Irvine, K. D. Hippo signaling in Drosophila: recent advances and insights. Dev. Dyn. 241, 3-15 (2012).
11. Karpowicz, P., Perez, J. & Perrimon, N. The Hippo tumor suppressor pathway regulates intestinal stem cell regeneration. Development 137, 4135-4145 (2010).
12. Shaw, R. L. et al. The Hippo pathway regulates intestinal stem cell proliferation during Drosophila adult midgut regeneration. Development 137, 4147-4158 (2010).
13. Wadham, C., Gamble, J. R., Vadas, M. A. & Khew-Goodall, Y. The protein tyrosine phosphatase Pez is a major phosphatase of adherens junctions and dephosphorylates β-catenin. Mol. Biol. Cell 14, 2520-2529 (2003).
14. Poernbacher, I., Baumgartner, R., Marada, S. K., Edwards, K. & Stocker, H. Drosophila Pez acts in Hippo signaling to restrict intestinal stem cell proliferation. Curr. Biol. 22, 389-396 (2012).
15. Hanratty, W. P. & Dearolf, C. R. The Drosophila Tumorous-lethal hematopoietic oncogene is a dominant mutation in the hopscotch locus. Mol. Gen. Genet. 238, 33-37 (1993).
16. Lacronique, V. et al. A TEL-JAK2 fusion protein with constitutive kinase activity in human leukemia. Science 278, 1309-1312 (1997).
17. Morata, G. & Ripoll, P. Minutes: mutants of Drosophila autonomously affecting cell division rate. Dev. Biol. 42, 211-221 (1975).
18. Baker, N. E. Cell competition. Curr. Biol. 21, R11-R15 (2011).
19. Johnston, L. A. Competitive interactions between cells: death, growth, and geography. Science 324, 1679-1682 (2009).
20. Morata, G. & Martin, F. A. Cell competition: the embrace of death. Dev. Cell 13, 1-2 (2007).
21. Moreno, E. Is cell competition relevant to cancer? Nature Rev. Cancer 8, 141-147 (2008).
22. Chen, C. L., Schroeder, M. C., Kango-Singh, M., Tao, C. & Halder, G. Tumor suppression by cell competition through regulation of the Hippo pathway. Proc. Natl Acad. Sci. USA 109, 484-489 (2012).
23. Lolo, F. N., Casas-Tinto, S. & Moreno, E. Cell competition time line: winners kill losers, which are extruded and engulfed by hemocytes. Cell Rep. 2, 526-539 (2012).
24. Portela, M. et al. Drosophila SPARC is a self-protective signal expressed by loser cells during cell competition. Dev. Cell 19, 562-573 (2010).
25. Menendez, J., Perez-Garijo, A., Calleja, M. & Morata, G. A tumor-suppressing mechanism in Drosophila involving cell competition and the Hippo pathway. Proc. Natl Acad. Sci. USA 107, 14651-14656 (2010).
26. Schroeder, M. C., Chen, C. L., Gajewski, K. & Halder, G. A non-cell-autonomous tumor suppressor role for Stat in eliminating oncogenic scribble cells. Oncogene 29 Oct 2012 (doi:10.1038/ onc.2012.476).
27. Rodrigues, A. B. et al. Activated STAT regulates growth and induces competitive interactions independently of Myc, Yorkie, Wingless and ribosome biogenesis. Development 139, 4051-4061 (2012).
28. Vincent, J. P., Kolahgar, G., Gagliardi, M. & Piddini, E. Steep differences in wingless signaling trigger Myc-independent competitive cell interactions. Dev. Cell 21, 366-374 (2011).
29. Ohsawa, S. et al. Elimination of oncogenic neighbors by JNK-mediated engulfment in Drosophila. Dev. Cell 20, 315-328 (2011).
30. Cordero, J. B. et al. Oncogenic Ras diverts a host TNF tumor suppressor activity into tumor promoter. Dev. Cell 18, 999-1011 (2010).
31. Sunkel, C. E. & Glover, D. M. polo, a mitotic mutant of Drosophila displaying abnormal spindle poles. J. Cell Sci. 89, 25-38 (1988).
32. Glover, D. M., Leibowitz, M. H., McLean, D. A. & Parry, H. Mutations in aurora prevent centrosome separation leading to the formation of monopolar spindles. Cell 81, 95-105 (1995).
33. Vader, G. & Lens, S. M. The Aurora kinase family in cell division and cancer. Biochim. Biophys. Acta 1786, 60-72 (2008).
34. Archambault, V. & Glover, D. M. Polo-like kinases: conservation and divergence in their functions and regulation. Nature Rev. Mol. Cell Biol. 10, 265-275 (2009).
35. de Carcer, G., Manning, G. & Malumbres, M. From Plk1 to Plk5: functional evolution of polo-like kinases. Cell Cycle 10, 2255-2262 (2011).
36. de Carcer, G., Perez de Castro, I. & Malumbres, M. Targeting cell cycle kinases for cancer therapy. Curr. Med. Chem. 14, 969-985 (2007).
37. Yamashita, Y. M., Jones, D. L. & Fuller, M. T. Orientation of asymmetric stem cell division by the APC tumor suppressor and centrosome. Science 301, 1547-1550 (2003).
38. Roberts, D. M., Pronobis, M. I., Poulton, J. S., Kane, E. G. & Peifer, M. 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, 2041-2056 (2012).
39. Takacs, C. M. et al. Dual positive and negative regulation of wingless signaling by adenomatous polyposis coli. Science 319, 333-336 (2008).
40. Cheng, L. Y. et al. Anaplastic lymphoma kinase spares organ growth during nutrient restriction in Drosophila. Cell 146, 435-447 (2011).
41. Klovstad, M., Abdu, U. & Schupbach, T. Drosophila brca2 is required for mitotic and meiotic DNA repair and efficient activation of the meiotic recombination checkpoint. PLoS Genet. 466, e31 (2008).
42. Thomas, B. J. & Wassarman, D. A. A fly's eye view of biology. Trends Genet. 15, 184-190 (1999).
43. Grzeschik, N. A., Parsons, L. M., Allott, M. L., Harvey, K. F. & Richardson, H. E. Lgl, aPKC, and Crumbs regulate the Salvador/Warts/Hippo pathway through two distinct mechanisms. Curr. Biol. 20, 573-581 (2010).
44. Poon, C. L., Lin, J. I., Zhang, X. & Harvey, K. F. The sterile 20-like kinase Tao-1 controls tissue growth by regulating the Salvador-Warts-Hippo pathway. Dev. Cell 21, 896-906 (2011).
45. Song, Z., Saghafi, N., Gokhale, V., Brabant, M. & Meuillet, E. J. Regulation of the activity of the tumor suppressor PTEN by thioredoxin in Drosophila melanogaster. Exp. Cell Res. 313, 1161-1171 (2007).
46. Rao, P. R., Makhijani, K. & Shashidhara, L. S. Human APC sequesters β-catenin even in the absence of GSK-3β in a Drosophila model. Oncogene 27, 2488-2493 (2008).
47. Kim, R. H. et al. DJ-1, a novel regulator of the tumor suppressor PTEN. Cancer Cell 7, 263-273 (2005).
48. Martinsson, T. et al. Appearance of the novel activating F1174S ALK mutation in neuroblastoma correlates with aggressive tumor progression and unresponsiveness to therapy. Cancer Res. 71, 98-105 (2011).
49. Chand, D. et al. Cell and Drosophila model systems define three classes of ALK mutations in neuroblastoma. Dis. Model. Mech. 25 Oct 2012 (doi:10.1242/dmm.010348).
50. Pereira, P. S. et al. E-cadherin missense mutations, associated with hereditary diffuse gastric cancer (HDGC) syndrome, display distinct invasive behaviors and genetic interactions with the Wnt and Notch pathways in Drosophila epithelia. Hum. Mol. Genet. 15, 1704-1712 (2006).
51. Caldeira, J. et al. CPEB1, a novel gene silenced in gastric cancer: a Drosophila approach. Gut 61, 1115-1123 (2012).
52. Botham, C. M., Wandler, A. M. & Guillemin, K. A transgenic Drosophila model demonstrates that the Helicobacter pylori CagA protein functions as a eukaryotic Gab adaptor. PLoS Pathog. 466, e1000064 (2008).
53. Miles, W. O., Dyson, N. J. & Walker, J. A. Modeling tumor invasion and metastasis in Drosophila. Dis. Model. Mech. 4, 753-761 (2011).
54. Salomon, R. N. & Jackson, F. R. Tumors of testis and midgut in aging flies. Fly 2, 265-268 (2008).
55. Golubovsky, M. D., Weisman, N. Y., Arbeev, K. G., Ukraintseva, S. V. & Yashin, A. I. Decrease in the lgl tumor suppressor dose in Drosophila increases survival and longevity in stress conditions. Exp. Gerontol. 41, 819-827 (2006).
56. Gonzalez, C. Spindle orientation, asymmetric division and tumour suppression in Drosophila stem cells. Nature Rev. Genet. 8, 462-472 (2007).
57. Watson, K. L., Justice, R. W. & Bryant, P. J. Drosophila in cancer research: the first fifty tumor suppressor genes. J. Cell Sci. Suppl. 18, 19-33 (1994).
58. Gateff, E. Malignant neoplasms of genetic origin in Drosophila melanogaster. Science 200, 1448-1459 (1978).
59. Bilder, D. Epithelial polarity and proliferation control: links from the Drosophila neoplastic tumor suppressors. Genes Dev. 18, 1909-1925 (2004).
60. Harris, H., Miller, O. J., Klein, G., Worst, P. & Tachibana, T. Suppression of malignancy by cell fusion. Nature 223, 363-368 (1969).
61. Harris, H. A long view of fashions in cancer research. Bioessays 27, 833-838 (2005).
62. Singh, S. R., Liu, W. & Hou, S. X. The adult Drosophila malpighian tubules are maintained by multipotent stem cells. Cell Stem Cell 1, 191-203 (2007).
63. Zeng, X., Singh, S. R., Hou, D. & Hou, S. X. Tumor suppressors Sav/Scrib and oncogene Ras regulate stem-cell transformation in adult Drosophila malpighian tubules. J. Cell. Physiol. 224, 766-774 (2010).
64. Neumuller, R. A. et al. Genome-wide analysis of self-renewal in Drosophila neural stem cells by transgenic RNAi. Cell Stem Cell 8, 580-593 (2011).
65. Pagliarini, R. A. & Xu, T. A genetic screen in Drosophila for metastatic behavior. Science 302, 1227-1231 (2003).
66. Brumby, A. M. & Richardson, H. E. scribble mutants cooperate with oncogenic Ras or Notch to cause neoplastic overgrowth in Drosophila. EMBO J. 22, 5769-5779 (2003).
67. Wu, M., Pastor-Pareja, J. C. & Xu, T. Interaction between RasV12 and scribbled clones induces tumour growth and invasion. Nature 463, 545-548 (2010).
68. Elsum, I., Yates, L., Humbert, P. O. & Richardson, H. E. The Scribble-Dlg-Lgl polarity module in development and cancer: from flies to man. Essays Biochem. 53, 141-168 (2012).
69. Pearson, H. B. et al. SCRIB expression is deregulated in human prostate cancer, and its deficiency in mice promotes prostate neoplasia. J. Clin. Invest. 121, 4257-4267 (2011).
70. Ohsawa, S. et al. Mitochondrial defect drives non-autonomous tumour progression through Hippo signalling in Drosophila. Nature 490, 547-551 (2012).
71. Wallace, D. C. Mitochondria and cancer. Nature Rev. Cancer 12, 685-698 (2012).
72. Dekanty, A., Barrio, L., Muzzopappa, M., Auer, H. & Milan, M. Aneuploidy-induced delaminating cells drive tumorigenesis in Drosophila epithelia. Proc. Natl Acad. Sci. USA 109, 20549-20554 (2012).
73. Perez-Garijo, A., Shlevkov, E. & Morata, G. 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, 1169-1177 (2009).
74. Read, R. D., Cavenee, W. K., Furnari, F. B. & Thomas, J. B. A Drosophila model for EGFR-Ras and PI3K-dependent human glioma. PLoS Genet. 566, e1000374 (2009).
75. Witte, H. T., Jeibmann, A., Klambt, C. & Paulus, W. Modeling glioma growth and invasion in Drosophila melanogaster. Neoplasia 11, 882-888 (2009).
76. Wang, Q. et al. Pax genes in embryogenesis and oncogenesis. J. Cell. Mol. Med. 12, 2281-2294 (2008).
77. Galindo, R. L., Allport, J. A. & Olson, E. N. A. Drosophila model of the rhabdomyosarcoma initiator PAX7-FKHR. Proc. Natl Acad. Sci. USA 103, 13439-13444 (2006).
78. Avirneni-Vadlamudi, U. et al. Drosophila and mammalian models uncover a role for the myoblast fusion gene TANC1 in rhabdomyosarcoma. J. Clin. Invest. 122, 403-407 (2012).
79. Jung, S. H., Evans, C. J., Uemura, C. & Banerjee, U. The Drosophila lymph gland as a developmental model of hematopoiesis. Development 132, 2521-2533 (2005).
80. Martinez-Agosto, J. A., Mikkola, H. K., Hartenstein, V. & Banerjee, U. The hematopoietic stem cell and its niche: a comparative view. Genes Dev. 21, 3044-3060 (2007).
81. Higuchi, M. et al. Expression of a conditional AML1-ETO oncogene bypasses embryonic lethality and establishes a murine model of human t(8;21) acute myeloid leukemia. Cancer Cell 1, 63-74 (2002).
82. Sinenko, S. A. et al. Genetic manipulation of AML1-ETO-induced expansion of hematopoietic precursors in a Drosophila model. Blood 116, 4612-4620 (2010).
83. Osman, D. et al. A Drosophila model identifies calpains as modulators of the human leukemogenic fusion protein AML1-ETO. Proc. Natl Acad. Sci. USA 106, 12043-12048 (2009).
84. Wandler, A. M. & Guillemin, K. Transgenic expression of the Helicobacter pylori virulence factor CagA promotes apoptosis or tumorigenesis through JNK activation in Drosophila. PLoS Pathog. 866, e1002939 (2012).
85. Ohlstein, B. & Spradling, A. The adult Drosophila posterior midgut is maintained by pluripotent stem cells. Nature 439, 470-474 (2006).
86. Micchelli, C. A. & Perrimon, N. Evidence that stem cells reside in the adult Drosophila midgut epithelium. Nature 439, 475-479 (2006).
87. Cordero, J., Vidal, M. & Sansom, O. APC as a master regulator of intestinal homeostasis and transformation: from flies to vertebrates. Cell Cycle 8, 2926-2931 (2009).
88. Cordero, J. B., Stefanatos, R. K., Scopelliti, A., Vidal, M. & Sansom, O. J. Inducible progenitor-derived Wingless regulates adult midgut regeneration in Drosophila. EMBO J. 31, 3901-3917 (2012).
89. Lee, W. C., Beebe, K., Sudmeier, L. & Micchelli, C. A. Adenomatous polyposis coli regulates Drosophila intestinal stem cell proliferation. Development 136, 2255-2264 (2009).
90. Apidianakis, Y., Pitsouli, C., Perrimon, N. & Rahme, L. Synergy between bacterial infection and genetic predisposition in intestinal dysplasia. Proc. Natl Acad. Sci. USA 106, 20883-20888 (2009).
91. Jiang, H. & Edgar, B. A. Intestinal stem cell function in Drosophila and mice. Curr. Opin. Genet. Dev. 22, 354-360 (2012).
92. Jiang, H., Grenley, M. O., Bravo, M. J., Blumhagen, R. Z. & Edgar, B. A. EGFR/Ras/MAPK signaling mediates adult midgut epithelial homeostasis and regeneration in Drosophila. Cell Stem Cell 8, 84-95 (2011).
93. Jiang, H. et al. Cytokine/Jak/Stat signaling mediates regeneration and homeostasis in the Drosophila midgut. Cell 137, 1343-1355 (2009).
94. Negrini, S., Gorgoulis, V. G. & Halazonetis, T. D. Genomic instability-an evolving hallmark of cancer. Nature Rev. Mol. Cell Biol. 11, 220-228 (2010).
95. Holland, A. J. & Cleveland, D. W. Losing balance: the origin and impact of aneuploidy in cancer. EMBO Rep. 13, 501-514 (2012).
96. McGranahan, N., Burrell, R. A., Endesfelder, D., Novelli, M. R. & Swanton, C. Cancer chromosomal instability: therapeutic and diagnostic challenges. EMBO Rep. 13, 528-538 (2012).
97. Pfau, S. J. & Amon, A. Chromosomal instability and aneuploidy in cancer: from yeast to man. EMBO Rep. 13, 515-527 (2012).
98. Raffa, G. D., Ciapponi, L., Cenci, G. & Gatti, M. Terminin: a protein complex that mediates epigenetic maintenance of Drosophila telomeres. Nucleus 2, 383-391 (2011).
99. Muller, H. J. An analysis of the process of structural change in chromosomes of Drosophila. J. Genet. 40, 1-66 (1940).
100. Titen, S. W. & Golic, K. G. Telomere loss provokes multiple pathways to apoptosis and produces genomic instability in Drosophila melanogaster. Genetics 180, 1821-1832 (2008).
101. Morciano, P. et al. A conserved role for the mitochondrial citrate transporter Sea/SLC25A1 in the maintenance of chromosome integrity. Hum. Mol. Genet. 18, 4180-4188 (2009).
102. Fox, D. T., Gall, J. G. & Spradling, A. C. Error-prone polyploid mitosis during normal Drosophila development. Genes Dev. 24, 2294-2302 (2010).
103. Anderhub, S. J., Kramer, A. & Maier, B. Centrosome amplification in tumorigenesis. Cancer Lett. 322, 8-17 (2012).
104. Caussinus, E. & Gonzalez, C. Induction of tumor growth by altered stem-cell asymmetric division in Drosophila melanogaster. Nature Genet. 37, 1125-1129 (2005).
105. Basto, R. et al. Centrosome amplification can initiate tumorigenesis in flies. Cell 133, 1032-1042 (2008).
106. Ganem, N. J., Godinho, S. A. & Pellman, D. A mechanism linking extra centrosomes to chromosomal instability. Nature 460, 278-282 (2009).
107. Silkworth, W. T., Nardi, I. K., Scholl, L. M. & Cimini, D. Multipolar spindle pole coalescence is a major source of kinetochore mis-attachment and chromosome mis-segregation in cancer cells. PLoS ONE 466, e6564 (2009).
108. Crasta, K. et al. DNA breaks and chromosome pulverization from errors in mitosis. Nature 482, 53-58 (2012).
109. Castellanos, E., Dominguez, P. & Gonzalez, C. Centrosome dysfunction in Drosophila neural stem cells causes tumors that are not due to genome instability. Curr. Biol. 18, 1209-1214 (2008).
110. Kusano, K., Berres, M. E. & Engels, W. R. Evolution of the RECQ family of helicases: a Drosophila homolog, Dmblm, is similar to the human bloom syndrome gene. Genetics 151, 1027-1039 (1999).
111. Garcia, A. M. et al. Loss of the bloom syndrome helicase increases DNA ligase 4-independent genome rearrangements and tumorigenesis in aging Drosophila. Genome Biol. 1266, R121 (2011).
112. Amor-Gueret, M. Bloom syndrome, genomic instability and cancer: the SOS-like hypothesis. Cancer Lett. 236, 1-12 (2006).
113. Wu, M. et al. Imaging hematopoietic precursor division in real time. Cell Stem Cell 1, 541-554 (2007).
114. Westhoff, B. et al. Alterations of the Notch pathway in lung cancer. Proc. Natl Acad. Sci. USA 106, 22293-22298 (2009).
115. Cicalese, A. et al. The tumor suppressor p53 regulates polarity of self-renewing divisions in mammary stem cells. Cell 138, 1083-1095 (2009).
116. Sugiarto, S. et al. Asymmetry-defective oligodendrocyte progenitors are glioma precursors. Cancer Cell 20, 328-340 (2011).
117. Goulas, S., Conder, R. & Knoblich, J. A. The par complex and integrins direct asymmetric cell division in adult intestinal stem cells. Cell Stem Cell 11, 529-540 (2012).
118. Egger, B., Chell, J. M. & Brand, A. H. Insights into neural stem cell biology from flies. Phil. Trans. R. Soc. B 363, 39-56 (2008).
119. Knoblich, J. A. Mechanisms of asymmetric stem cell division. Cell 132, 583-597 (2008).
120. Egger, B., Gold, K. S. & Brand, A. H. Regulating the balance between symmetric and asymmetric stem cell division in the developing brain. Fly 5, 237-241 (2011).
121. Martin-Belmonte, F. & Perez-Moreno, M. Epithelial cell polarity, stem cells and cancer. Nature Rev. Cancer 12, 23-38 (2012).
122. Chang, K. C., Wang, C. & Wang, H. Balancing self-renewal and differentiation by asymmetric division: insights from brain tumor suppressors in Drosophila neural stem cells. Bioessays 34, 301-310 (2012).
123. Januschke, J. & Gonzalez, C. Drosophila asymmetric division, polarity and cancer. Oncogene 27, 6994-7002 (2008).
124. Wang, H. et al. Aurora-A acts as a tumor suppressor and regulates self-renewal of Drosophila neuroblasts. Genes Dev. 20, 3453-3463 (2006).
125. Wang, H., Ouyang, Y., Somers, W. G., Chia, W. & Lu, B. Polo inhibits progenitor self-renewal and regulates Numb asymmetry by phosphorylating Pon. Nature 449, 96-100 (2007).
126. Lee, C. Y. et al. Drosophila Aurora-A kinase inhibits neuroblast self-renewal by regulating aPKC/Numb cortical polarity and spindle orientation. Genes Dev. 20, 3464-3474 (2006).
127. Brachmann, S., Fritsch, C., Maira, S. M. & Garcia-Echeverria, C. PI3K and mTOR inhibitors: a new generation of targeted anticancer agents. Curr. Opin. Cell Biol. 21, 194-198 (2009).
128. Willecke, M., Toggweiler, J. & Basler, K. Loss of PI3K blocks cell-cycle progression in a Drosophila tumor model. Oncogene 30, 4067-4074 (2011).
129. Rossi, F. & Gonzalez, C. Synergism between altered cortical polarity and the PI3K/TOR pathway in the suppression of tumour growth. EMBO Rep. 13, 157-162 (2011).
130. Martins, T., Maia, A. F., Steffensen, S. & Sunkel, C. E. Sgt1, a co-chaperone of Hsp90 stabilizes Polo and is required for centrosome organization. EMBO J. 28, 234-247 (2009).
131. Andersen, R. O., Turnbull, D. W., Johnson, E. A. & Doe, C. Q. Sgt1 acts via an LKB1/AMPK pathway to establish cortical polarity in larval neuroblasts. Dev. Biol. 363, 258-265 (2012).
132. Bonaccorsi, S. et al. The Drosophila Lkb1 kinase is required for spindle formation and asymmetric neuroblast division. Development 134, 2183-2193 (2007).
133. Yamamoto, Y., Izumi, Y. & Matsuzaki, F. The GC kinase Fray and Mo25 regulate Drosophila asymmetric divisions. Biochem. Biophys. Res. Commun. 366, 212-218 (2008).
134. Martin, S. G. & St Johnston, D. A role for Drosophila LKB1 in anterior-posterior axis formation and epithelial polarity. Nature 421, 379-384 (2003).
135. Mirouse, V., Swick, L. L., Kazgan, N., St Johnston, D. & Brenman, J. E. LKB1 and AMPK maintain epithelial cell polarity under energetic stress. J. Cell Biol. 177, 387-392 (2007).
136. Richly, H., Aloia, L. & Di Croce, L. Roles of the Polycomb group proteins in stem cells and cancer. Cell Death Dis. 266, e204 (2011).
137. Ferres-Marco, D. et al. Epigenetic silencers and Notch collaborate to promote malignant tumours by Rb silencing. Nature 439, 430-436 (2006).
138. Martinez, A. M. et al. Polyhomeotic has a tumor suppressor activity mediated by repression of Notch signaling. Nature Genet. 41, 1076-1082 (2009).
139. Feng, S., Thomas, S. & Wang, J. Diverse tumor pathology due to distinctive patterns of JAK/STAT pathway activation caused by different Drosophila polyhomeotic alleles. Genetics 190, 279-282 (2012).
140. Gonzalez, I., Simon, R. & Busturia, A. The Polyhomeotic protein induces hyperplastic tissue overgrowth through the activation of the JAK/STAT pathway. Cell Cycle 8, 4103-4111 (2009).
141. Classen, A. K., Bunker, B. D., Harvey, K. F., Vaccari, T. & Bilder, D. A tumor suppressor activity of Drosophila Polycomb genes mediated by JAK-STAT signaling. Nature Genet. 41, 1150-1155 (2009).
142. Simpson, A. J., Caballero, O. L., Jungbluth, A., Chen, Y. T. & Old, L. J. Cancer/testis antigens, gametogenesis and cancer. Nature Rev. Cancer 5, 615-625 (2005).
143. Curran, S. P., Wu, X., Riedel, C. G. & Ruvkun, G. A soma-to-germline transformation in long-lived Caenorhabditis elegans mutants. Nature 459, 1079-1084 (2009).
144. Geldmacher, A., Freier, A., Losch, F. O. & Walden, P. Therapeutic vaccination for cancer immunotherapy: antigen selection and clinical responses. Hum. Vaccin. 7, 115-119 (2011).
145. Gateff, E., Loffler, T. & Wismar, J. A temperature-sensitive brain tumor suppressor mutation of Drosophila melanogaster: developmental studies and molecular localization of the gene. Mech. Dev. 41, 15-31 (1993).
146. Janic, A., Mendizabal, L., Llamazares, S., Rossell, D. & Gonzalez, C. Ectopic expression of germline genes drives malignant brain tumor growth in Drosophila. Science 330, 1824-1827 (2010).
147. Meier, K. et al. LINT, a novel dL(3)mbt-containing complex, represses malignant brain tumour signature genes. PLoS Genet. 866, e1002676 (2012).
148. Georlette, D. et al. Genomic profiling and expression studies reveal both positive and negative activities for the Drosophila Myb MuvB/dREAM complex in proliferating cells. Genes Dev. 21, 2880-2896 (2007).
149. Munos, B. Lessons from 60 years of pharmaceutical innovation. Nature Rev. Drug Discov. 8, 959-968 (2009).
150. Pandey, U. B. & Nichols, C. D. Human disease models in Drosophila melanogaster and the role of the fly in therapeutic drug discovery. Pharmacol. Rev. 63, 411-436 (2011).
151. Gladstone, M. & Su, T. T. Chemical genetics and drug screening in Drosophila cancer models. J. Genet. Genom. 38, 497-504 (2011).
152. Kim, B. H. et al. A small-molecule compound identified through a cell-based screening inhibits JAK/STAT pathway signaling in human cancer cells. Mol. Cancer Ther. 7, 2672-2680 (2008).
153. Kim, B. H. et al. MS-1020 is a novel small molecule that selectively inhibits JAK3 activity. Br. J. Haematol. 148, 132-143 (2010).
154. Kim, B. H. et al. Benzoxathiol derivative BOT-4-one suppresses L540 lymphoma cell survival and proliferation via inhibition of JAK3/STAT3 signaling. Exp. Mol. Med. 43, 313-321 (2011).
155. Gonsalves, F. C. et al. An RNAi-based chemical genetic screen identifies three small-molecule inhibitors of the Wnt/wingless signaling pathway. Proc. Natl Acad. Sci. USA 108, 5954-5963 (2011).
156. Read, R. D. et al. A Drosophila model of multiple endocrine neoplasia type 2. Genetics 171, 1057-1081 (2005).
157. Vidal, M., Wells, S., Ryan, A. & Cagan, R. ZD6474 suppresses oncogenic RET isoforms in a Drosophila model for type 2 multiple endocrine neoplasia syndromes and papillary thyroid carcinoma. Cancer Res. 65, 3538-3541 (2005).
158. Das, T. & Cagan, R. Drosophila as a novel therapeutic discovery tool for thyroid cancer. Thyroid 20, 689-695 (2010).
159. Dar, A. C., Das, T. K., Shokat, K. M. & Cagan, R. L. Chemical genetic discovery of targets and anti-targets for cancer polypharmacology. Nature 486, 80-84 (2012).
160. Jaklevic, B. et al. Contribution of growth and cell cycle checkpoints to radiation survival in Drosophila. Genetics 174, 1963-1972 (2006).
161. Edwards, A. et al. Combinatorial effect of maytansinol and radiation in Drosophila and human cancer cells. Dis. Model. Mech. 4, 496-503 (2011).
162. Jolad, S. D. et al. Bouvardin and deoxybouvardin, antitumor cyclic hexapeptides from Bouvardia ternifolia (Rubiaceae). J. Am. Chem. Soc. 99, 8040-8044 (1977).
163. Gladstone, M. et al. 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, 342-350 (2012).
164. Willoughby, L. F. et al. An in vivo large-scale chemical screening platform using Drosophila for anti-cancer drug discovery. Dis. Model. Mech. 20 Sep 2012 (doi:10.1242/dmm.009985).
165. Hardy, P. A. & Zacharias, H. Reappraisal of the Hansemann-Boveri hypothesis on the origin of tumors. Cell Biol. Int. 29, 983-992 (2005).
166. Dickson, B. & Hafen, E. in The Development of Drosophila Melanogaster (eds Bate, M. & Martinez-Arias, A.) 1327-1362 (Cold Spring Harbor Laboratory Press, 1993).
167. Morris, E. J. et al. E2F1 represses β-catenin transcription and is antagonized by both pRB and CDK8. Nature 455, 552-556 (2008).
168. Bello, B., Reichert, H. & Hirth, F. The brain tumor gene negatively regulates neural progenitor cell proliferation in the larval central brain of Drosophila. Development 133, 2639-2648 (2006).