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

Key Points

  • For a century, seemingly non-applied research carried out in Drosophila melanogaster has provided the first glimpse into the mechanism of action of human cancer-related proteins.

  • Natural malignant tumours can occur in D. melanogaster.

  • Tumours can also be experimentally induced in larvae and adult flies either by knocking down fly tumour suppressor genes or by recreating in flies the mutant conditions that are causative of certain human cancer types. Current examples of this 'a la carte' design include cancer models of glioblastoma, rhabdomyosarcoma, multiple endocrine neoplasia and leukaemia.

  • D. melanogaster tumours range from hyperplasias to frankly malignant neoplasias that are invasive and lethal to the host.

  • Both the presence and the lack of supernumerary centrosomes can cause tumours in the larval brain, but unbalanced karyotypes do not. Thus, in D. melanogaster, Boveri's hypothesis does not apply, but centrosome dysfunction is linked to cancer.

  • The origin of the widespread genome instability that is characteristic of cancer cells is likely to be multifactorial.

  • The loss of cell polarity in cells that divide asymmetrically, as well as in epithelial tissues, is often tumorigenic.

  • The Aurora and POLO protein kinases are tumour suppressors in the larval brain.

  • The activation of signalling pathways that sense low calorie intake and inhibit target of rapamycin (TOR) compromises cortical polarity and contributes to tumour growth.

  • Data derived from D. melanogaster strongly substantiate the view that timely repression of gene expression programmes during development has a pronounced tumour suppression function.

  • D. melanogaster lethal (3) malignant brain tumour (l(3)mbt) tumours recapitulate the ectopic expression of cancer germline (CG; also known as cancer testis (CT)) genes that are observed in many types of somatic human tumours. In D. melanogaster, inactivation of some CG genes inhibits tumour growth.

  • D. melanogaster is starting to have an important role in chemical genetics, helping to identify the pathways that are affected by current pharmaceuticals, facilitating the design of more efficient derivatives and serving as a platform for semi-automated screens for new anticancer drugs.

Abstract

For decades, lower-model organisms such as Drosophila melanogaster have often provided the first glimpse into the mechanism of action of human cancer-related proteins, thus making a substantial contribution to elucidating the molecular basis of the disease. More recently, D. melanogaster strains that are engineered to recapitulate key aspects of specific types of human cancer have been paving the way for the future role of this 'workhorse' of biomedical research, helping to further investigate the process of malignancy, and serving as platforms for therapeutic drug discovery.

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Figure 1: Using eye development for functional assays.
Figure 2: Tumours in flies.
Figure 3: Different routes to genomic instability.
Figure 4: Testing Boveri's hypothesis in flies.
Figure 5: Whole-organism screening in Drosophila melanogaster larvae.

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Acknowledgements

The author is very grateful to T. T. Su, Y. Zheng, S. Llamazares, E. Scheenaard, J. Januschke, J. Reina, F. Rossi, J. Petrovic, J. Pampalona and G. Pollarollo for critical reading of the manuscript. Research in the author's laboratory is funded by grants BFU2009-07975/BMC, BFU2012-32522, CENIT ONCOLOGICA-20091016, SGR Agaur 2009 CG041413 and ERC-2011-AdG 294603.

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Correspondence to Cayetano Gonzalez.

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Glossary

Genetic screens

Experimental technique aimed at identifying mutant genes that cause a particular phenotype.

D. melanogaster neuroblasts

Precursors that generate neural tissue.

Rhabdomyosarcoma

Malignancy of muscle myoblasts that fail to exit the cell cycle and do not fuse into syncytial skeletal muscle.

Syncytial skeletal muscle

Muscle made of multinucleated cells, also known as fibres, formed by the fusion of thousands of individual myoblast cells.

Differentiation therapy

Reprogramming neoplastic cells to terminally differentiate.

Multipolar spindles

Spindles that have more than two poles.

Lagging chromosomes

Chromosomes that fail poleward anaphase movement.

Apico-basal cortical polarity

An unequal build-up of certain molecules on either the apical or the basal side of the cell.

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Gonzalez, C. Drosophila melanogaster: a model and a tool to investigate malignancy and identify new therapeutics. Nat Rev Cancer 13, 172–183 (2013). https://doi.org/10.1038/nrc3461

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