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Review
. 2015 Apr;1(3):190-9.
doi: 10.1159/000370155. Epub 2015 Apr 9.

Drosophila as a Potential Model for Ocular Tumors

Daimark Bennett  1 , Ekaterina Lyulcheva  2 , Neville Cobbe  1
Affiliations
Review

Drosophila as a Potential Model for Ocular Tumors

Daimark Bennett et al. Ocul Oncol Pathol. 2015 Apr.

Abstract

Drosophila has made many contributions to our understanding of cancer genes and mechanisms that have subsequently been validated in mammals. Despite anatomical differences between fly and human eyes, flies offer a tractable genetic model in which to dissect the functional importance of genetic lesions found to be affected in human ocular tumors. Here, we discuss different approaches for using Drosophila as a model for ocular cancer and how studies on ocular cancer genes in flies have begun to reveal potential strategies for therapeutic intervention. We also discuss recent developments in the use of Drosophila for drug discovery, which is coming to the fore as Drosophila models are becoming tailored to study tumor types found in the clinic.

Keywords: Cancer model; Drosophila; Ocular cancer; Ocular oncology; Retinoblastoma; Uveal melanoma.

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Figures

Fig. 1
Fig. 1
Utilizing the genetic toolkit in Drosophila for cancer studies. The GAL4/UAS expression system [65] (a) and the FLP/FRT system [66] (b) are two of the most commonly used tools to manipulate gene function in Drosophila. a The GAL4/UAS bipartite expression system allows flexible overexpression or knockdown of a gene of interest in different tissues or stages of development. Flies carrying one of many available GAL4 lines are crossed to flies carrying the gene of interest under the control of the UAS element. Binding of GAL4 to the UAS element in the progeny drives the expression in the pattern of the GAL4 line. Publicly available genome-wide RNA interference and overexpression UAS libraries [67,68] have broadened the utility of this approach. Temperature-sensitive alleles of GAL80, a repressor of GAL4-mediated gene expression, can also be employed in this system for further temporal control of expression (not shown). b The Flp/FRT system can be used to generate clones of mutant cells in otherwise normal tissues. Expression of the Flp gene, for example under the control of a heat shock (hs) promoter, results in recombination between two FRT (Flp recombination target) sites on sister chromatids. One of the resulting daughter cells is consequently homozygous mutant for the gene of interest and is negatively labeled by the absence of GFP, whereas GFP expression labels both the parental cell and the other daughter cell, which are heterozygous and homozygous wild type for the gene of interest, respectively. This system can be coupled with GAL80 to positively label mutant cells lacking the repressor (not shown). c Combining the approaches outlined in a and b, it is possible to generate clones of cells ectopically expressing an activated oncogene whilst simultaneously harboring additional mutations that affect the properties of the resulting tumors (see Pagliarini and Xu [12] for details). For instance, cells overexpressing RasV12 in the developing eye lead to localized non-invasive tumors. The presence of additional metastasis-inducing factors (e.g. gene X) drives the formation of secondary tumors visualized by the presence of GFP in other parts of the larva.
Fig. 2
Fig. 2
Strategies for testing the ability of chemical inhibitors to suppress the effects of RETMEN2 overexpression in Drosophila. a Eye-specific expression: ectopic overexpression of RETMEN2 under the control of the GMR promoter results in a fully penetrant rough eye phenotype in adults (red lines). Flies fed with vandetanib (ZD6474) strongly rescue defective eye development (blue line) [35]. b Expression in developing epithelia (wing, eye and leg) and other tissues: ectopic expression of UAS-RETMEN2 under the control of ptc-GAL4 results in lethality early in development (red line). This assay was used to screen a library of polypharmacological compounds capable of restoring viability (blue line). Further chemical refinement of initial hits identified a compound, AD80, with optimal efficacy and toxicity compared to analogs [37]. Colors refer to the online version only.
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