Glioblastoma Models in Drosophila Melanogaster

Abstract

Gliomas comprise the most common and most malignant intrinsic human brain tumours, with a very poor prognosis. Despite some recent therapeutic progress, there is still a large demand for novel drug targets to cope with the high recurrence rate. In the present article, we introduce the Drosophila model as a new tool in deciphering the mechanisms underlying the generation and progression of glial tumours. Despite the fact that Drosophila has only few glial cells and no vascular system with patrolling lymphocytes, the basic principles underlying glioblastoma biology appear very well conserved. The role of epidermal growth factor (EGF) receptor pathways, PVR (PDGF‐ and VEGF‐receptor related) and phophatidylinositol 3‐kinase (PI3K) signalling in Drosophila glioma models is discussed.

Key Concepts:

  • Gliomas are the most common and most malignant intrinsic human brain tumours, with a very poor prognosis.

  • In majority of the glioblastoma, the molecular cause of malignancy is due to an amplification of receptor tyrosine kinase genes. The role of EGF‐receptor pathways, PVR and PI3K signalling in Drosophila glioma models is introduced in the text.

  • Glial cell proliferation and glial cell migration is controlled by evolutionary conserved mechanisms.

  • The insect Drosophila melanogaster has a very simple structured nervous and glial cells perform similar tasks as their vertebrate counterparts.

  • The model organism Drosophila provides a rich source to decipher the mechanisms underlying the biology of human glioma and can be used to define novel drug targets.

Keywords: Drosophila; glial cells; tumour model; glioblastoma

References

Arama E, Dickman D, Kimchie Z, Shearn A and Lev Z (2000) Mutations in the beta‐propeller domain of the Drosophila brain tumor (brat) protein induce neoplasm in the larval brain. Oncogene 19: 3706–3716.

Awasaki T, Lai SL, Ito K and Lee T (2008) Organization and postembryonic development of glial cells in the adult central brain of Drosophila. Journal of Neuroscience 28: 13742–13753.

Bainton RJ, Tsai LT, Schwabe T et al. (2005) Moody encodes two GPCRs that regulate cocaine behaviors and blood‐brain barrier permeability in Drosophila. Cell 123: 145–156.

Beaucher M, Goodliffe J, Hersperger E et al. (2007) Drosophila brain tumor metastases express both neuronal and glial cell type markers. Developmental Biology 301: 287–297.

Betschinger J, Mechtler K and Knoblich JA (2006) Asymmetric segregation of the tumor suppressor brat regulates self‐renewal in Drosophila neural stem cells. Cell 124: 1241–1253.

Bier E (2005) Drosophila, the golden bug, emerges as a tool for human genetics. Nature Reviews. Genetics 6: 9–23.

Bilen J and Bonini NM (2005) Drosophila as a model for human neurodegenerative disease. Annual Review of Genetics 39: 153–171.

Brand AH and Perrimon N (1993) Targeted gene expression as a means of altering cell fates and generating dominant phenotypes. Development 118: 401–415.

Brumby AM and Richardson HE (2005) Using Drosophila melanogaster to map human cancer pathways. Nature Reviews. Cancer 5: 626–639.

Dietzl G, Chen D, Schnorrer F et al. (2007) A genome‐wide transgenic RNAi library for conditional gene inactivation in Drosophila. Nature 448: 151–156.

Doherty J, Logan MA, Tasdemir OE and Freeman MR (2009) Ensheathing glia function as phagocytes in the adult Drosophila brain. Journal of Neuroscience 29: 4768–4781.

Duffy JB (2002) GAL4 system in Drosophila: a fly geneticist's Swiss army knife. Genesis 34: 1–15.

Endersby R and Baker SJ (2008) PTEN signaling in brain: neuropathology and tumorigenesis. Oncogene 27: 5416–5430.

Franzdottir SR, Engelen D, Yuva‐Aydemir Y et al. (2009) Switch in FGF signalling initiates glial differentiation in the Drosophila eye. Nature 460: 758–761.

Furnari FB, Fenton T, Bachoo RM et al. (2007) Malignant astrocytic glioma: genetics, biology, and paths to treatment. Genes & Development 21: 2683–2710.

Gateff E (1978) Malignant neoplasms of genetic origin in Drosophila melanogaster. Science 200: 1448–1459.

Hamaratoglu F, Willecke M, Kango‐Singh M et al. (2006) The tumour‐suppressor genes NF2/Merlin and expanded act through Hippo signalling to regulate cell proliferation and apoptosis. Nature Cell Biology 8: 27–36.

Holland EC, Celestino J, Dai C et al. (2000) Combined activation of Ras and Akt in neural progenitors induces glioblastoma formation in mice. Nature Genetics 25: 55–57.

Jeibmann A and Paulus W (2009) Drosophila melanogaster as a model organism of brain diseases. International Journal of Molecular Sciences 10: 407–440.

Klambt C (2009) Modes and regulation of glial migration in vertebrates and invertebrates. Nature Reviews. Neuroscience 10: 769–779.

Lai SL and Lee T (2006) Genetic mosaic with dual binary transcriptional systems in Drosophila. Nature Neuroscience 9: 703–709.

Lee T and Luo L (1999) Mosaic analysis with a repressible cell marker for studies of gene function in neuronal morphogenesis. Neuron 22: 451–461.

Li J, Xia F and Li WX (2003) Coactivation of STAT and Ras is required for germ cell proliferation and invasive migration in Drosophila. Developmental Cell 5: 787–798.

Louis DN, Ohgaki H, Wiestler OD et al. (2007) The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathologica 114: 97–109.

McGuire SE, Le PT, Osborn AJ, Matsumoto K and Davis RL (2003) Spatiotemporal rescue of memory dysfunction in Drosophila. Science 302: 1765–1768.

McGuire SE, Mao Z and Davis RL (2004a) Spatiotemporal gene expression targeting with the TARGET and gene‐switch systems in Drosophila. Science's STKE: Signal Transduction Knowledge Environment 2004: pl6.

McGuire SE, Roman G and Davis RL (2004b) Gene expression systems in Drosophila: a synthesis of time and space. Trends in Genetics 20: 384–391.

Nicholson L, Singh GK, Osterwalder T et al. (2008) Spatial and temporal control of gene expression in Drosophila using the inducible GeneSwitch GAL4 system. I. Screen for larval nervous system drivers. Genetics 178: 215–234.

Ohgaki H and Kleihues P (2005) Epidemiology and etiology of gliomas. Acta Neuropathologica 109: 93–108.

Omuro AM and Delattre JY (2008) What is the place of bevacizumab and irinotecan in the treatment of glioblastoma and other malignant gliomas? Current Opinion in Neurology 21: 717–719.

Read RD, Cavenee WK, Furnari FB and Thomas JB (2009) A Drosophila model for EGFR‐Ras and PI3K‐dependent human glioma. PLoS Genetics 5: e1000374.

Read RD, Goodfellow PJ, Mardis ER et al. (2005) A Drosophila model of multiple endocrine neoplasia type 2. Genetics 171: 1057–1081.

Schwabe T, Bainton RJ, Fetter RD, Heberlein U and Gaul U (2005) GPCR signaling is required for blood‐brain barrier formation in Drosophila. Cell 123: 133–144.

Silies M, Yuva Y, Engelen D et al. (2007) Glial cell migration in the eye disc. Journal of Neuroscience 27: 13130–13139.

Stork T, Engelen D, Krudewig A et al. (2008) Organization and function of the blood‐brain barrier in Drosophila. Journal of Neuroscience 28: 587–597.

Stork T, Thomas S, Rodrigues F et al. (2009) Drosophila neurexin IV stabilizes neuron‐glia interactions at the CNS midline by binding to wrapper. Development 136: 1251–1261.

Vidal M and Cagan RL (2006) Drosophila models for cancer research. Current Opinion in Genetics & Development 16: 10–16.

Wismar J, Loffler T, Habtemichael N et al. (1995) The Drosophila melanogaster tumor suppressor gene lethal(3)malignant brain tumor encodes a proline‐rich protein with a novel zinc finger. Mechanics of Development 53: 141–154.

Witte HT, Jeibmann A, Klambt C and Paulus W (2009) Modeling glioma growth and invasion in Drosophila melanogaster. Neoplasia 11: 882–888.

Woodhouse E, Hersperger E and Shearn A (1998) Growth, metastasis, and invasiveness of Drosophila tumors caused by mutations in specific tumor suppressor genes. Development Genes and Evolution 207: 542–550.

Zheng H, Ying H, Yan H et al. (2008a) p53 and Pten control neural and glioma stem/progenitor cell renewal and differentiation. Nature 455: 1129–1133.

Zheng H, Ying H, Yan H et al. (2008b) Pten and p53 converge on c‐Myc to control differentiation, self‐renewal, and transformation of normal and neoplastic stem cells in glioblastoma. Cold Spring Harbor Symposia on Quantitative Biology 73: 427–437.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Jeibmann, A, Kim, SN, Paulus, W, and Klämbt, C(Sep 2010) Glioblastoma Models in Drosophila Melanogaster. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0022540]