Drosophila melanogaster as a Model System for Human Glioblastomas

  • Alexander S. Chen
  • Renee D. ReadEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1167)


Glioblastoma multiforme (GBM) is the most common primary malignant adult brain tumor. Genomic amplifications, activating mutations, and overexpression of receptor tyrosine kinases (RTKs) such as EGFR, and genes in core RTK signaling transduction pathways such as PI3K are common in GBM. However, efforts to target these pathways have been largely unsuccessful in the clinic, and the median survival of GBM patients remains poor at 14–15 months. Therefore, to improve patient outcomes, there must be a concerted effort to elucidate the underlying biology involved in GBM tumorigenesis. Drosophila melanogaster has been a highly effective model for furthering our understanding of GBM tumorigenesis due to a number of experimental advantages it has over traditional mouse models. For example, there exists extensive cellular and genetic homology between humans and Drosophila, and 75% of genes associated with human disease have functional fly orthologs. To take advantage of these traits, we developed a Drosophila GBM model with constitutively active variants of EGFR and PI3K that effectively recapitulated key aspects of GBM disease. Researchers have utilized this model in forward genetic screens and have expanded on its functionality to make a number of important discoveries regarding requirements for key components in GBM tumorigenesis, including genes and pathways involved in extracellular matrix signaling, glycolytic metabolism, invasion/migration, stem cell fate and differentiation, and asymmetric cell division. Drosophila will continue to reveal novel biological pathways and mechanisms involved in gliomagenesis, and this knowledge may contribute to the development of effective treatment strategies to improve patient outcomes.


Glia Glioblastoma EGFR Phosphatidyl-inositol-3-kinase PI3K Neoplasia 



We thank Dr. Nathaniel H. Boyd and Hye Rim Kim for critical reading of this manuscript.


  1. 1.
    Weller M, van den Bent M, Tonn JC, Stupp R, Preusser M, Cohen-Jonathan-Moyal E, Henriksson R, Le Rhun E, Balana C, Chinot O, Bendszus M, Reijneveld JC, Dhermain F, French P, Marosi C, Watts C, Oberg I, Pilkington G, Baumert BG, Taphoorn MJB, Hegi M, Westphal M, Reifenberger G, Soffietti R, Wick W (2017) European Association for Neuro-Oncology (EANO) guideline on the diagnosis and treatment of adult astrocytic and oligodendroglial gliomas. Lancet Oncol 18(6):e315–e329. Scholar
  2. 2.
    Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Scheithauer BW, Kleihues P (2007) The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 114(2):97–109. Scholar
  3. 3.
    Cancer Genome Atlas Research Network (2008) Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455(7216):1061–1068. Scholar
  4. 4.
    Brennan CW, Verhaak RG, McKenna A, Campos B, Noushmehr H, Salama SR, Zheng S, Chakravarty D, Sanborn JZ, Berman SH, Beroukhim R, Bernard B, Wu CJ, Genovese G, Shmulevich I, Barnholtz-Sloan J, Zou L, Vegesna R, Shukla SA, Ciriello G, Yung WK, Zhang W, Sougnez C, Mikkelsen T, Aldape K, Bigner DD, Van Meir EG, Prados M, Sloan A, Black KL, Eschbacher J, Finocchiaro G, Friedman W, Andrews DW, Guha A, Iacocca M, O'Neill BP, Foltz G, Myers J, Weisenberger DJ, Penny R, Kucherlapati R, Perou CM, Hayes DN, Gibbs R, Marra M, Mills GB, Lander E, Spellman P, Wilson R, Sander C, Weinstein J, Meyerson M, Gabriel S, Laird PW, Haussler D, Getz G, Chin L (2013) The somatic genomic landscape of glioblastoma. Cell 155(2):462–477. Scholar
  5. 5.
    Humphrey PA, Wong AJ, Vogelstein B, Zalutsky MR, Fuller GN, Archer GE, Friedman HS, Kwatra MM, Bigner SH, Bigner DD (1990) Anti-synthetic peptide antibody reacting at the fusion junction of deletion-mutant epidermal growth factor receptors in human glioblastoma. Proc Natl Acad Sci U S A 87(11):4207–4211CrossRefGoogle Scholar
  6. 6.
    Wong AJ, Ruppert JM, Bigner SH, Grzeschik CH, Humphrey PA, Bigner DS, Vogelstein B (1992) Structural alterations of the epidermal growth factor receptor gene in human gliomas. Proc Natl Acad Sci U S A 89(7):2965–2969CrossRefGoogle Scholar
  7. 7.
    Boockvar JA, Kapitonov D, Kapoor G, Schouten J, Counelis GJ, Bogler O, Snyder EY, McIntosh TK, O'Rourke DM (2003) Constitutive EGFR signaling confers a motile phenotype to neural stem cells. Mol Cell Neurosci 24(4):1116–1130CrossRefGoogle Scholar
  8. 8.
    Bachoo RM, Maher EA, Ligon KL, Sharpless NE, Chan SS, You MJ, Tang Y, DeFrances J, Stover E, Weissleder R, Rowitch DH, Louis DN, DePinho RA (2002) Epidermal growth factor receptor and Ink4a/Arf: convergent mechanisms governing terminal differentiation and transformation along the neural stem cell to astrocyte axis. Cancer Cell 1(3):269–277CrossRefGoogle Scholar
  9. 9.
    Ozawa T, Brennan CW, Wang L, Squatrito M, Sasayama T, Nakada M, Huse JT, Pedraza A, Utsuki S, Yasui Y, Tandon A, Fomchenko EI, Oka H, Levine RL, Fujii K, Ladanyi M, Holland EC (2010) PDGFRA gene rearrangements are frequent genetic events in PDGFRA-amplified glioblastomas. Genes Dev 24(19):2205–2218. Scholar
  10. 10.
    Nagane M, Levitzki A, Gazit A, Cavenee WK, Huang HJ (1998) Drug resistance of human glioblastoma cells conferred by a tumor-specific mutant epidermal growth factor receptor through modulation of Bcl-XL and caspase-3-like proteases. Proc Natl Acad Sci U S A 95(10):5724–5729CrossRefGoogle Scholar
  11. 11.
    Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S, Yan H, Gazdar A, Powell SM, Riggins GJ, Willson JK, Markowitz S, Kinzler KW, Vogelstein B, Velculescu VE (2004) High frequency of mutations of the PIK3CA gene in human cancers. Science (New York, NY) 304(5670):554. Scholar
  12. 12.
    Gallia GL, Rand V, Siu IM, Eberhart CG, James CD, Marie SK, Oba-Shinjo SM, Carlotti CG, Caballero OL, Simpson AJ, Brock MV, Massion PP, Carson BS Sr, Riggins GJ (2006) PIK3CA gene mutations in pediatric and adult glioblastoma multiforme. Mol Cancer Res 4(10):709–714. Scholar
  13. 13.
    Mizoguchi M, Nutt CL, Mohapatra G, Louis DN (2004) Genetic alterations of phosphoinositide 3-kinase subunit genes in human glioblastomas. Brain Pathol (Zurich, Switzerland) 14(4):372–377CrossRefGoogle Scholar
  14. 14.
    Haas-Kogan D, Shalev N, Wong M, Mills G, Yount G, Stokoe D (1998) Protein kinase B (PKB/Akt) activity is elevated in glioblastoma cells due to mutation of the tumor suppressor PTEN/MMAC. Curr Biol 8(21):1195–1198CrossRefGoogle Scholar
  15. 15.
    Baeza N, Weller M, Yonekawa Y, Kleihues P, Ohgaki H (2003) PTEN methylation and expression in glioblastomas. Acta Neuropathol 106(5):479–485. Scholar
  16. 16.
    Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, Puc J, Miliaresis C, Rodgers L, McCombie R, Bigner SH, Giovanella BC, Ittmann M, Tycko B, Hibshoosh H, Wigler MH, Parsons R (1997) PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science (New York, NY) 275(5308):1943–1947CrossRefGoogle Scholar
  17. 17.
    Lee Y, Koh J, Kim SI, Won JK, Park CK, Choi SH, Park SH (2017) The frequency and prognostic effect of TERT promoter mutation in diffuse gliomas. Acta Neuropathol Commun 5(1):62. Scholar
  18. 18.
    Furnari FB, Fenton T, Bachoo RM, Mukasa A, Stommel JM, Stegh A, Hahn WC, Ligon KL, Louis DN, Brennan C, Chin L, DePinho RA, Cavenee WK (2007) Malignant astrocytic glioma: genetics, biology, and paths to treatment. Genes Dev 21(21):2683–2710. Scholar
  19. 19.
    Holland EC, Celestino J, Dai C, Schaefer L, Sawaya RE, Fuller GN (2000) Combined activation of Ras and Akt in neural progenitors induces glioblastoma formation in mice. Nat Genet 25(1):55–57. Scholar
  20. 20.
    Li L, Dutra A, Pak E, Labrie JE 3rd, Gerstein RM, Pandolfi PP, Recht LD, Ross AH (2009) EGFRvIII expression and PTEN loss synergistically induce chromosomal instability and glial tumors. Neuro-Oncology 11(1):9–21. Scholar
  21. 21.
    Zheng H, Ying H, Yan H, Kimmelman AC, Hiller DJ, Chen AJ, Perry SR, Tonon G, Chu GC, Ding Z, Stommel JM, Dunn KL, Wiedemeyer R, You MJ, Brennan C, Wang YA, Ligon KL, Wong WH, Chin L, dePinho RA (2008) Pten and p53 converge on c-Myc to control differentiation, self-renewal, and transformation of normal and neoplastic stem cells in glioblastoma. Cold Spring Harb Symp Quant Biol 73:427–437. Scholar
  22. 22.
    Fomchenko EI, Dougherty JD, Helmy KY, Katz AM, Pietras A, Brennan C, Huse JT, Milosevic A, Holland EC (2011) Recruited cells can become transformed and overtake PDGF-induced murine gliomas in vivo during tumor progression. PLoS One 6(7):e20605. Scholar
  23. 23.
    Holland EC, Hively WP, DePinho RA, Varmus HE (1998) A constitutively active epidermal growth factor receptor cooperates with disruption of G1 cell-cycle arrest pathways to induce glioma-like lesions in mice. Genes Dev 12(23):3675–3685CrossRefGoogle Scholar
  24. 24.
    Cloughesy TF, Yoshimoto K, Nghiemphu P, Brown K, Dang J, Zhu S, Hsueh T, Chen Y, Wang W, Youngkin D, Liau L, Martin N, Becker D, Bergsneider M, Lai A, Green R, Oglesby T, Koleto M, Trent J, Horvath S, Mischel PS, Mellinghoff IK, Sawyers CL (2008) Antitumor activity of rapamycin in a Phase I trial for patients with recurrent PTEN-deficient glioblastoma. PLoS Med 5(1):e8. Scholar
  25. 25.
    Mellinghoff IK, Wang MY, Vivanco I, Haas-Kogan DA, Zhu S, Dia EQ, Lu KV, Yoshimoto K, Huang JH, Chute DJ, Riggs BL, Horvath S, Liau LM, Cavenee WK, Rao PN, Beroukhim R, Peck TC, Lee JC, Sellers WR, Stokoe D, Prados M, Cloughesy TF, Sawyers CL, Mischel PS (2005) Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. N Engl J Med 353(19):2012–2024. Scholar
  26. 26.
    Raizer JJ, Abrey LE, Lassman AB, Chang SM, Lamborn KR, Kuhn JG, Yung WK, Gilbert MR, Aldape KA, Wen PY, Fine HA, Mehta M, Deangelis LM, Lieberman F, Cloughesy TF, Robins HI, Dancey J, Prados MD (2010) A phase II trial of erlotinib in patients with recurrent malignant gliomas and nonprogressive glioblastoma multiforme postradiation therapy. Neuro-Oncology 12(1):95–103. Scholar
  27. 27.
    Szerlip NJ, Pedraza A, Chakravarty D, Azim M, McGuire J, Fang Y, Ozawa T, Holland EC, Huse JT, Jhanwar S, Leversha MA, Mikkelsen T, Brennan CW (2012) Intratumoral heterogeneity of receptor tyrosine kinases EGFR and PDGFRA amplification in glioblastoma defines subpopulations with distinct growth factor response. Proc Natl Acad Sci U S A 109(8):3041–3046. Scholar
  28. 28.
    Gonzalez C (2013) Drosophila melanogaster: a model and a tool to investigate malignancy and identify new therapeutics. Nat Rev Cancer 13(3):172–183. Scholar
  29. 29.
    Lee T, Luo L (1999) Mosaic analysis with a repressible cell marker for studies of gene function in neuronal morphogenesis. Neuron 22(3):451–461CrossRefGoogle Scholar
  30. 30.
    Bellen HJ, Levis RW, Liao G, He Y, Carlson JW, Tsang G, Evans-Holm M, Hiesinger PR, Schulze KL, Rubin GM, Hoskins RA, Spradling AC (2004) The BDGP gene disruption project: single transposon insertions associated with 40% of Drosophila genes. Genetics 167(2):761–781. Scholar
  31. 31.
    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
  32. 32.
    Dietzl G, Chen D, Schnorrer F, Su KC, Barinova Y, Fellner M, Gasser B, Kinsey K, Oppel S, Scheiblauer S, Couto A, Marra V, Keleman K, Dickson BJ (2007) A genome-wide transgenic RNAi library for conditional gene inactivation in Drosophila. Nature 448(7150):151–156. Scholar
  33. 33.
    St Johnston D (2002) The art and design of genetic screens: Drosophila melanogaster. Nat Rev Genet 3(3):176–188. Scholar
  34. 34.
    Reiter LT, Potocki L, Chien S, Gribskov M, Bier E (2001) A systematic analysis of human disease-associated gene sequences in Drosophila melanogaster. Genome Res 11(6):1114–1125. Scholar
  35. 35.
    Freeman MR (2015) Drosophila central nervous system glia. Cold Spring Harb Perspect Biol 7(11). Scholar
  36. 36.
    Speder P, Brand AH (2018) Systemic and local cues drive neural stem cell niche remodelling during neurogenesis in Drosophila. elife 7.
  37. 37.
    Read RD (2018) Pvr receptor tyrosine kinase signaling promotes post-embryonic morphogenesis, and survival of glia and neural progenitor cells in Drosophila. Development 145(23). Scholar
  38. 38.
    Coutinho-Budd JC, Sheehan AE, Freeman MR (2017) The secreted neurotrophin Spatzle 3 promotes glial morphogenesis and supports neuronal survival and function. Genes Dev 31(20):2023–2038. Scholar
  39. 39.
    Leiserson WM, Harkins EW, Keshishian H (2000) Fray, a Drosophila serine/threonine kinase homologous to mammalian PASK, is required for axonal ensheathment. Neuron 28(3):793–806CrossRefGoogle Scholar
  40. 40.
    Auld VJ, Fetter RD, Broadie K, Goodman CS (1995) Gliotactin, a novel transmembrane protein on peripheral glia, is required to form the blood-nerve barrier in Drosophila. Cell 81(5):757–767CrossRefGoogle Scholar
  41. 41.
    Gateff E (1978) Malignant neoplasms of genetic origin in Drosophila melanogaster. Science (New York, NY) 200(4349):1448–1459CrossRefGoogle Scholar
  42. 42.
    Gateff E (1994) Tumor suppressor and overgrowth suppressor genes of Drosophila melanogaster: developmental aspects. Int J Dev Biol 38(4):565–590PubMedGoogle Scholar
  43. 43.
    St John MA, Xu T (1997) Understanding human cancer in a fly? Am J Hum Genet 61(5):1006–1010. Scholar
  44. 44.
    Artavanis-Tsakonas S, Muskavitch MA, Yedvobnick B (1983) Molecular cloning of Notch, a locus affecting neurogenesis in Drosophila melanogaster. Proc Natl Acad Sci U S A 80(7):1977–1981CrossRefGoogle Scholar
  45. 45.
    Fan X, Khaki L, Zhu TS, Soules ME, Talsma CE, Gul N, Koh C, Zhang J, Li YM, Maciaczyk J, Nikkhah G, Dimeco F, Piccirillo S, Vescovi AL, Eberhart CG (2010) NOTCH pathway blockade depletes CD133-positive glioblastoma cells and inhibits growth of tumor neurospheres and xenografts. Stem Cells (Dayton, Ohio) 28(1):5–16. Scholar
  46. 46.
    Read RD, Cavenee WK, Furnari FB, Thomas JB (2009) A drosophila model for EGFR-Ras and PI3K-dependent human glioma. PLoS Genet 5(2):e1000374. Scholar
  47. 47.
    Read RD, Fenton TR, Gomez GG, Wykosky J, Vandenberg SR, Babic I, Iwanami A, Yang H, Cavenee WK, Mischel PS, Furnari FB, Thomas JB (2013) A kinome-wide RNAi screen in Drosophila Glia reveals that the RIO kinases mediate cell proliferation and survival through TORC2-Akt signaling in glioblastoma. PLoS Genet 9(2):e1003253. Scholar
  48. 48.
    Park NI, Guilhamon P, Desai K, McAdam RF, Langille E, O'Connor M, Lan X, Whetstone H, Coutinho FJ, Vanner RJ, Ling E, Prinos P, Lee L, Selvadurai H, Atwal G, Kushida M, Clarke ID, Voisin V, Cusimano MD, Bernstein M, Das S, Bader G, Arrowsmith CH, Angers S, Huang X, Lupien M, Dirks PB (2017) ASCL1 reorganizes chromatin to direct neuronal fate and suppress Tumorigenicity of Glioblastoma stem cells. Cell Stem Cell 21(3):411. Scholar
  49. 49.
    Witte HT, Jeibmann A, Klambt C, Paulus W (2009) Modeling glioma growth and invasion in Drosophila melanogaster. Neoplasia (New York, NY) 11(9):882–888CrossRefGoogle Scholar
  50. 50.
    Chen AS, Wardwell-Ozgo J, Shah NN, Wright D, Appin CL, Vigneswaran K, Brat DJ, Kornblum HI, Read RD (2018) Drak/STK17A drives neoplastic glial proliferation through modulation of MRLC signaling. Cancer Res. Scholar
  51. 51.
    Chen X, Wanggou S, Bodalia A, Zhu M, Dong W, Fan JJ, Yin WC, Min HK, Hu M, Draghici D, Dou W, Li F, Coutinho FJ, Whetstone H, Kushida MM, Dirks PB, Song Y, Hui CC, Sun Y, Wang LY, Li X, Huang X (2018) A feedforward mechanism mediated by Mechanosensitive Ion Channel PIEZO1 and tissue mechanics promotes Glioma aggression. Neuron 100(4):799–815.e797. Scholar
  52. 52.
    Frattini V, Pagnotta SM, Tala FJJ, Russo MV, Lee SB, Garofano L, Zhang J, Shi P, Lewis G, Sanson H, Frederick V, Castano AM, Cerulo L, Rolland DCM, Mall R, Mokhtari K, Elenitoba-Johnson KSJ, Sanson M, Huang X, Ceccarelli M, Lasorella A, Iavarone A (2018) A metabolic function of FGFR3-TACC3 gene fusions in cancer. Nature 553(7687):222–227. Scholar
  53. 53.
    Kim SN, Jeibmann A, Halama K, Witte HT, Walte M, Matzat T, Schillers H, Faber C, Senner V, Paulus W, Klambt C (2014) ECM stiffness regulates glial migration in Drosophila and mammalian glioma models. Development 141(16):3233–3242. Scholar
  54. 54.
    Chi KC, Tsai WC, Wu CL, Lin TY, Hueng DY (2018) An adult Drosophila Glioma model for studying Pathometabolic pathways of Gliomagenesis. Mol Neurobiol. Scholar
  55. 55.
    Agnihotri S, Golbourn B, Huang X, Remke M, Younger S, Cairns RA, Chalil A, Smith CA, Krumholtz SL, Mackenzie D, Rakopoulos P, Ramaswamy V, Taccone MS, Mischel PS, Fuller GN, Hawkins C, Stanford WL, Taylor MD, Zadeh G, Rutka JT (2016) PINK1 is a negative regulator of growth and the Warburg effect in Glioblastoma. Cancer Res 76(16):4708–4719. Scholar
  56. 56.
    Cheng P, Wang J, Waghmare I, Sartini S, Coviello V, Zhang Z, Kim SH, Mohyeldin A, Pavlyukov MS, Minata M, Valentim CL, Chhipa RR, Bhat KP, Dasgupta B, La Motta C, Kango-Singh M, Nakano I (2016) FOXD1-ALDH1A3 signaling is a determinant for the self-renewal and Tumorigenicity of Mesenchymal Glioma stem cells. Cancer Res 76(24):7219–7230. Scholar
  57. 57.
    Silies M, Yuva Y, Engelen D, Aho A, Stork T, Klambt C (2007) Glial cell migration in the eye disc. J Neurosci Off J Soc Neurosci 27(48):13130–13139. Scholar
  58. 58.
    Green P, Hartenstein AY, Hartenstein V (1993) The embryonic development of the Drosophila visual system. Cell Tissue Res 273(3):583–598CrossRefGoogle Scholar
  59. 59.
    Rich JN, Reardon DA, Peery T, Dowell JM, Quinn JA, Penne KL, Wikstrand CJ, Van Duyn LB, Dancey JE, McLendon RE, Kao JC, Stenzel TT, Ahmed Rasheed BK, Tourt-Uhlig SE, Herndon JE 2nd, Vredenburgh JJ, Sampson JH, Friedman AH, Bigner DD, Friedman HS (2004) Phase II trial of gefitinib in recurrent glioblastoma. J Clin Oncol Off J Am Soc Clin Oncol 22(1):133–142. Scholar
  60. 60.
    Zong H, Parada LF, Baker SJ (2015) Cell of origin for malignant gliomas and its implication in therapeutic development. Cold Spring Harb Perspect Biol 7(5). Scholar
  61. 61.
    Funa K, Sasahara M (2014) The roles of PDGF in development and during neurogenesis in the normal and diseased nervous system. J Neuroimmune Pharmacol 9(2):168–181. Scholar
  62. 62.
    Tanaka K, Babic I, Nathanson D, Akhavan D, Guo D, Gini B, Dang J, Zhu S, Yang H, De Jesus J, Amzajerdi AN, Zhang Y, Dibble CC, Dan H, Rinkenbaugh A, Yong WH, Vinters HV, Gera JF, Cavenee WK, Cloughesy TF, Manning BD, Baldwin AS, Mischel PS (2011) Oncogenic EGFR signaling activates an mTORC2-NF-kappaB pathway that promotes chemotherapy resistance. Cancer Discov 1 (6):524–538. doi: 2159-8290.CD-11-0124 [pii] 63.1158/2159-8290.CD-11-0124Google Scholar
  63. 63.
    Sunayama J, Sato A, Matsuda K, Tachibana K, Watanabe E, Seino S, Suzuki K, Narita Y, Shibui S, Sakurada K, Kayama T, Tomiyama A, Kitanaka C (2011) FoxO3a functions as a key integrator of cellular signals that control glioblastoma stem-like cell differentiation and tumorigenicity. Stem cells (Dayton, Ohio) 29(9):1327–1337. Scholar
  64. 64.
    Masui K, Tanaka K, Akhavan D, Babic I, Gini B, Matsutani T, Iwanami A, Liu F, Villa GR, Gu Y, Campos C, Zhu S, Yang H, Yong WH, Cloughesy TF, Mellinghoff IK, Cavenee WK, Shaw RJ, Mischel PS (2013) mTOR complex 2 controls glycolytic metabolism in Glioblastoma through FoxO acetylation and Upregulation of c-Myc. Cell Metab 18:1–14CrossRefGoogle Scholar
  65. 65.
    Babic I, Anderson ES, Tanaka K, Guo D, Masui K, Li B, Zhu S, Gu Y, Villa GR, Akhavan D, Nathanson D, Gini B, Mareninov S, Li R, Camacho CE, Kurdistani SK, Eskin A, Nelson SF, Yong WH, Cavenee WK, Cloughesy TF, Christofk HR, Black DL, Mischel PS (2013) EGFR mutation-induced alternative splicing of Max contributes to growth of glycolytic tumors in brain cancer. Cell Metab 17(6):1000–1008. S1550-4131(13)00156-3 [pii] 10.1016/j.cmet.2013.04.013CrossRefGoogle Scholar
  66. 66.
    Vanrobays E, Gelugne JP, Gleizes PE, Caizergues-Ferrer M (2003) Late cytoplasmic maturation of the small ribosomal subunit requires RIO proteins in Saccharomyces cerevisiae. Mol Cell Biol 23(6):2083–2095CrossRefGoogle Scholar
  67. 67.
    Widmann B, Wandrey F, Badertscher L, Wyler E, Pfannstiel J, Zemp I, Kutay U (2011) The kinase activity of human Rio1 is required for final steps of cytoplasmic maturation of 40S subunits. Mol Biol Cell doi: mbc.E11-07-0639 [pii]
  68. 68.
    Zemp I, Wild T, O'Donohue MF, Wandrey F, Widmann B, Gleizes PE, Kutay U (2009) Distinct cytoplasmic maturation steps of 40S ribosomal subunit precursors require hRio2. J Cell Biol 185(7):1167–1180. Scholar
  69. 69.
    Baumas K, Soudet J, Caizergues-Ferrer M, Faubladier M, Henry Y, Mougin A (2012) Human RioK3 is a novel component of cytoplasmic pre-40S pre-ribosomal particles. RNA Biol 9(2):162–174. 18810 [pii] 10.4161/rna.18810CrossRefGoogle Scholar
  70. 70.
    Strunk BS, Novak MN, Young CL, Karbstein K (2012) A translation-like cycle is a quality control checkpoint for maturing 40S ribosome subunits. Cell 150 (1):111–121. doi: S0092-8674(12)00645-9 [pii]
  71. 71.
    Ferreira-Cerca S, Sagar V, Schafer T, Diop M, Wesseling AM, Lu H, Chai E, Hurt E, LaRonde-LeBlanc N (2012) ATPase-dependent role of the atypical kinase Rio2 on the evolving pre-40S ribosomal subunit. Nat Struct Mol Biol 19 (12):1316–1323. doi:nsmb.2403 [pii] 1038/nsmb.2403Google Scholar
  72. 72.
    Neubueser D, Hipfner DR (2010) Overlapping roles of Drosophila Drak and Rok kinases in epithelial tissue morphogenesis. Mol Biol Cell 21(16):2869–2879. Scholar
  73. 73.
    Bialik S, Kimchi A (2006) The death-associated protein kinases: structure, function, and beyond. Annu Rev Biochem 75:189–210. Scholar
  74. 74.
    Straight AF, Field CM, Mitchison TJ (2005) Anillin binds nonmuscle myosin II and regulates the contractile ring. Mol Biol Cell 16(1):193–201. Scholar
  75. 75.
    Heissler SM, Manstein DJ (2013) Nonmuscle myosin-2: mix and match. Cellular and molecular life sciences. CMLS 70(1):1–21. Scholar
  76. 76.
    Kasza KE, Zallen JA (2011) Dynamics and regulation of contractile actin-myosin networks in morphogenesis. Curr Opin Cell Biol 23(1):30–38. Scholar
  77. 77.
    Chougule AB, Hastert MC, Thomas JH (2016) Drak is required for Actomyosin organization during Drosophila Cellularization. G3 (Bethesda, Md) 6(4):819–828. Scholar
  78. 78.
    Singh D, Chan JM, Zoppoli P, Niola F, Sullivan R, Castano A, Liu EM, Reichel J, Porrati P, Pellegatta S, Qiu K, Gao Z, Ceccarelli M, Riccardi R, Brat DJ, Guha A, Aldape K, Golfinos JG, Zagzag D, Mikkelsen T, Finocchiaro G, Lasorella A, Rabadan R, Iavarone A (2012) Transforming fusions of FGFR and TACC genes in human glioblastoma. Science (New York, NY) 337(6099):1231–1235. Scholar
  79. 79.
    Di Stefano AL, Fucci A, Frattini V, Labussiere M, Mokhtari K, Zoppoli P, Marie Y, Bruno A, Boisselier B, Giry M, Savatovsky J, Touat M, Belaid H, Kamoun A, Idbaih A, Houillier C, Luo FR, Soria JC, Tabernero J, Eoli M, Paterra R, Yip S, Petrecca K, Chan JA, Finocchiaro G, Lasorella A, Sanson M, Iavarone A (2015) Detection, characterization, and inhibition of FGFR-TACC fusions in IDH Wild-type Glioma. Clin Cancer Res 21(14):3307–3317. Scholar
  80. 80.
    Miroshnikova YA, Mouw JK, Barnes JM, Pickup MW, Lakins JN, Kim Y, Lobo K, Persson AI, Reis GF, McKnight TR, Holland EC, Phillips JJ, Weaver VM (2016) Tissue mechanics promote IDH1-dependent HIF1alpha-tenascin C feedback to regulate glioblastoma aggression. Nat Cell Biol 18(12):1336–1345. Scholar
  81. 81.
    Kai F, Laklai H, Weaver VM (2016) Force matters: biomechanical regulation of cell invasion and migration in disease. Trends Cell Biol 26(7):486–497. Scholar
  82. 82.
    Northey JJ, Przybyla L, Weaver VM (2017) Tissue force programs cell fate and tumor aggression. Cancer Discov 7(11):1224–1237. Scholar
  83. 83.
    Oudin MJ, Weaver VM (2016) Physical and chemical gradients in the tumor microenvironment regulate tumor cell invasion, migration, and metastasis. Cold Spring Harb Symp Quant Biol 81:189–205. Scholar
  84. 84.
    Murthy SE, Dubin AE, Patapoutian A (2017) Piezos thrive under pressure: mechanically activated ion channels in health and disease. Nat Rev Mol Cell Biol 18(12):771–783. Scholar
  85. 85.
    Cox CD, Bae C, Ziegler L, Hartley S, Nikolova-Krstevski V, Rohde PR, Ng CA, Sachs F, Gottlieb PA, Martinac B (2016) Removal of the mechanoprotective influence of the cytoskeleton reveals PIEZO1 is gated by bilayer tension. Nat Commun 7:10366. Scholar
  86. 86.
    Lewis AH, Grandl J (2015) Mechanical sensitivity of Piezo1 ion channels can be tuned by cellular membrane tension. elife 4.
  87. 87.
    Kim SE, Coste B, Chadha A, Cook B, Patapoutian A (2012) The role of Drosophila Piezo in mechanical nociception. Nature 483(7388):209–212. Scholar
  88. 88.
    He L, Si G, Huang J, Samuel ADT, Perrimon N (2018) Mechanical regulation of stem-cell differentiation by the stretch-activated Piezo channel. Nature 555(7694):103–106. Scholar
  89. 89.
    Overington JP, Al-Lazikani B, Hopkins AL (2006) How many drug targets are there? Nat Rev Drug Discov 5(12):993–996. Scholar
  90. 90.
    Ulrich TA, de Juan Pardo EM, Kumar S (2009) The mechanical rigidity of the extracellular matrix regulates the structure, motility, and proliferation of glioma cells. Cancer Res 69(10):4167–4174. Scholar
  91. 91.
    Moore SW, Roca-Cusachs P, Sheetz MP (2010) Stretchy proteins on stretchy substrates: the important elements of integrin-mediated rigidity sensing. Dev Cell 19(2):194–206. Scholar
  92. 92.
    Bokel C, Brown NH (2002) Integrins in development: moving on, responding to, and sticking to the extracellular matrix. Dev Cell 3(3):311–321CrossRefGoogle Scholar
  93. 93.
    Ginsberg MH (2014) Integrin activation. BMB Rep 47(12):655–659CrossRefGoogle Scholar
  94. 94.
    Warburg O (1956) On respiratory impairment in cancer cells. Science (New York, NY) 124(3215):269–270Google Scholar
  95. 95.
    Deberardinis RJ, Sayed N, Ditsworth D, Thompson CB (2008) Brick by brick: metabolism and tumor cell growth. Curr Opin Genet Dev 18(1):54–61. Scholar
  96. 96.
    Vander Heiden MG, Cantley LC, Thompson CB (2009) Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science (New York, NY) 324(5930):1029–1033. Scholar
  97. 97.
    Gandhi S, Wood-Kaczmar A, Yao Z, Plun-Favreau H, Deas E, Klupsch K, Downward J, Latchman DS, Tabrizi SJ, Wood NW, Duchen MR, Abramov AY (2009) PINK1-associated Parkinson's disease is caused by neuronal vulnerability to calcium-induced cell death. Mol Cell 33(5):627–638. Scholar
  98. 98.
    Wang X, Winter D, Ashrafi G, Schlehe J, Wong YL, Selkoe D, Rice S, Steen J, LaVoie MJ, Schwarz TL (2011) PINK1 and Parkin target Miro for phosphorylation and degradation to arrest mitochondrial motility. Cell 147(4):893–906. Scholar
  99. 99.
    Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, Henkelman RM, Cusimano MD, Dirks PB (2004) Identification of human brain tumour initiating cells. Nature 432(7015):396–401. Scholar
  100. 100.
    Ignatova TN, Kukekov VG, Laywell ED, Suslov ON, Vrionis FD, Steindler DA (2002) Human cortical glial tumors contain neural stem-like cells expressing astroglial and neuronal markers in vitro. Glia 39(3):193–206. Scholar
  101. 101.
    Galli R, Binda E, Orfanelli U, Cipelletti B, Gritti A, De Vitis S, Fiocco R, Foroni C, Dimeco F, Vescovi A (2004) Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma. Cancer Res 64(19):7011–7021. Scholar
  102. 102.
    Laks DR, Masterman-Smith M, Visnyei K, Angenieux B, Orozco NM, Foran I, Yong WH, Vinters HV, Liau LM, Lazareff JA, Mischel PS, Cloughesy TF, Horvath S, Kornblum HI (2009) Neurosphere formation is an independent predictor of clinical outcome in malignant glioma. Stem Cells (Dayton, Ohio) 27(4):980–987. Scholar
  103. 103.
    Lathia JD, Mack SC, Mulkearns-Hubert EE, Valentim CL, Rich JN (2015) Cancer stem cells in glioblastoma. Genes Dev 29(12):1203–1217. Scholar
  104. 104.
    Hannenhalli S, Kaestner KH (2009) The evolution of fox genes and their role in development and disease. Nat Rev Genet 10(4):233–240. Scholar
  105. 105.
    Nakano I (2014) Transcription factors as master regulator for cancer stemness: remove milk from fox? Expert Rev Anticancer Ther 14(8):873–875. Scholar
  106. 106.
    Koga M, Matsuda M, Kawamura T, Sogo T, Shigeno A, Nishida E, Ebisuya M (2014) Foxd1 is a mediator and indicator of the cell reprogramming process. Nat Commun 5:3197. Scholar
  107. 107.
    Mao P, Joshi K, Li J, Kim SH, Li P, Santana-Santos L, Luthra S, Chandran UR, Benos PV, Smith L, Wang M, Hu B, Cheng SY, Sobol RW, Nakano I (2013) Mesenchymal glioma stem cells are maintained by activated glycolytic metabolism involving aldehyde dehydrogenase 1A3. Proc Natl Acad Sci U S A 110(21):8644–8649. Scholar
  108. 108.
    Berninger B, Guillemot F, Gotz M (2007) Directing neurotransmitter identity of neurones derived from expanded adult neural stem cells. Eur J Neurosci 25(9):2581–2590. Scholar
  109. 109.
    Chanda S, Ang CE, Davila J, Pak C, Mall M, Lee QY, Ahlenius H, Jung SW, Sudhof TC, Wernig M (2014) Generation of induced neuronal cells by the single reprogramming factor ASCL1. Stem Cell Rep 3(2):282–296. Scholar
  110. 110.
    Mukherjee S, Kong J, Brat DJ (2015) Cancer stem cell division: when the rules of asymmetry are broken. Stem Cells Dev 24(4):405–416. Scholar
  111. 111.
    Knoblich JA (2008) Mechanisms of asymmetric stem cell division. Cell 132(4):583–597. Scholar
  112. 112.
    Homem CC, Knoblich JA (2012) Drosophila neuroblasts: a model for stem cell biology. Development 139(23):4297–4310. Scholar
  113. 113.
    Caussinus E, Gonzalez C (2005) Induction of tumor growth by altered stem-cell asymmetric division in Drosophila melanogaster. Nat Genet 37(10):1125–1129. Scholar
  114. 114.
    Betschinger J, Mechtler K, Knoblich JA (2006) Asymmetric segregation of the tumor suppressor brat regulates self-renewal in Drosophila neural stem cells. Cell 124(6):1241–1253. Scholar
  115. 115.
    Chen G, Kong J, Tucker-Burden C, Anand M, Rong Y, Rahman F, Moreno CS, Van Meir EG, Hadjipanayis CG, Brat DJ (2014) Human Brat ortholog TRIM3 is a tumor suppressor that regulates asymmetric cell division in glioblastoma. Cancer Res 74(16):4536–4548. Scholar
  116. 116.
    Mukherjee S, Tucker-Burden C, Zhang C, Moberg K, Read R, Hadjipanayis C, Brat DJ (2016) Drosophila Brat and human Ortholog TRIM3 maintain stem cell equilibrium and suppress brain tumorigenesis by attenuating Notch nuclear transport. Cancer Res 76(8):2443–2452. Scholar
  117. 117.
    Mukherjee S, Tucker-Burden C, Kaissi E, Newsam A, Duggireddy H, Chau M, Zhang C, Diwedi B, Rupji M, Seby S, Kowalski J, Kong J, Read R, Brat DJ (2018) CDK5 inhibition resolves PKA/cAMP-independent activation of CREB1 signaling in Glioma stem cells. Cell Rep 23(6):1651–1664. Scholar
  118. 118.
    Bjornsson CS, Apostolopoulou M, Tian Y, Temple S (2015) It takes a village: constructing the neurogenic niche. Dev Cell 32(4):435–446. Scholar
  119. 119.
    Reitman ZJ, Sinenko SA, Spana EP, Yan H (2015) Genetic dissection of leukemia-associated IDH1 and IDH2 mutants and D-2-hydroxyglutarate in Drosophila. Blood 125(2):336–345. Scholar
  120. 120.
    Felsenfeld G (2014) A brief history of epigenetics. Cold Spring Harb Perspect Biol 6(1). Scholar
  121. 121.
    García MG, Carella A, Urdinguio RG, Bayón GF, Lopez V, Tejedor JR, Sierra MI, García-Toraño E, Santamarina P, Perez RF, Mangas C, Astudillo A, Corte-Torres MD, Sáenz-de-Santa-María I, Chiara MD, Fernández AF, Fraga MF (2018) Epigenetic dysregulation of TET2 in human glioblastoma. Oncotarget 9(40):25922–25934. Scholar
  122. 122.
    Wang F, Minakhina S, Tran H, Changela N, Kramer J, Steward R (2018) Tet protein function during Drosophila development. PLoS One 13(1):e0190367. Scholar
  123. 123.
    Das TK, Esernio J, Cagan RL (2018) Restraining network response to targeted Cancer therapies improves efficacy and reduces cellular resistance. Cancer Res 78(15):4344–4359. Scholar
  124. 124.
    Bergman P, Seyedoleslami Esfahani S, Engstrom Y (2017) Drosophila as a model for human diseases-focus on innate immunity in barrier epithelia. Curr Top Dev Biol 121:29–81. Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of Pharmacology and Chemical BiologyEmory University School of MedicineAtlantaUSA
  2. 2.Department of Hematology and Medical OncologyEmory University School of MedicineAtlantaUSA
  3. 3.Winship Cancer CenterEmory University School of MedicineAtlantaUSA

Personalised recommendations