Modelling Cancer in Drosophila : The Next Generation

Abstract

Drosophila melanogaster , the vinegar fly, has been utilised as a genetic amenable model organism for more than 100 years. In recent years, its use in modelling human cancer has been greatly expanding. In this article, an update of the recent advances in Drosophila research towards understanding cancer development is provided. Genetic analysis in Drosophila has provided considerable insight into the mechanisms controlling tissue growth and cell invasion/metastasis during tumourigenesis, as well as the importance of stem cells in tissue regeneration and cancer, and how genes cooperate in tumourigenesis. Several evolutionarily conserved signalling pathways are emerging as playing key roles in many of these processes, including the Jun kinase, Notch, Wnt, Jak/Stat and the Hippo tissue growth control pathway. Drosophila has also been specifically utilised to model certain human cancers, by expression of the human versions of cancer‐causing genes, including multiple endocrine neoplasia type 2, glioblastoma and acute myeloid leukaemia. Finally, the use of Drosophila as a vehicle for anticancer drug discovery is beginning to make an important impact in combating human cancer. Key Concepts: Drosophila is a useful system for modelling human cancer due to the high conservation of critical cancer‐causing genes between humans and flies. Many signalling pathways contribute to tissue growth; however, the Hippo growth control pathway is emerging as playing a major role. The Jun kinase signalling pathway plays a context‐dependent role in invasion/metastasis. Cell polarity and differentiation factors play important roles in controlling the behaviour of stem cells, which can be usurped in cancer. Cell competition mechanisms are important in removing damaged cells, and the perturbation of this control contributes to tumourigenesis. Cancer is a cooperative process and Drosophila research has revealed many cooperating oncogenes and tumour suppressors. Drosophila provides a useful model system to investigate specific human cancers including multiple endocrine neoplasia type 2, glioblastoma and acute myeloid leukaemia. Drosophila can be utilised to screen for anticancer drugs.

Modelling Cooperative Tumorigenesis inDrosophila

“…The development of malignant cancer requires the deregulation of many processes, including increased cell proliferation, reduced differentiation and apoptosis, increased invasion, and altered metabolism (reviewed in [ 157 ]). There are only a few tumour-causing genes that when individually knocked down or overexpressed in whole epithelial tissues or large domains, are capable of inducing all the hallmarks of cancer that can be modelled in Drosophila (reviewed in [ 3 , 11 , 15 , 158 ]). Many genes, when deregulated, can cause hyperplastic tumours, characterized by increased tissue growth that are still capable of differentiating, but only a few result in neoplastic tumours, in which the tissue overgrows and shows reduced differentiation and a loss of tissue architecture (reviewed in [ 159 ]).…”

“…Use of Drosophila as a model organism for cancer research was pioneered by genetic screens, conducted in the late 1900s, which identified many Drosophila tumour-causing mutations (reviewed in [ 16 , 17 ]). Many of these were novel tumour-suppressor genes or oncogenes, which were subsequently shown to also have tumourigenic properties in mammalian systems and to be involved in human cancer (reviewed in [ 8 , 9 , 11 , 18 , 19 ]).…”

Regulation of Notch signaling and endocytosis by the Lgl neoplastic tumor suppressor

“…Decades of fundamental research utilizing the vinegar fly, Drosophila melanogaster, have revealed many important genes and signalling networks that have subsequently proven to be important in human cancer (reviewed by [1][2][3][4]. Of particular interest for epithelial and neural cancers are the junctional neoplastic tumor suppressors, Lgl, Discs large (Dlg) and Scribbled (Scrib) (reviewed by 5 ).…”

Cooperation of the BTB-Zinc finger protein, Abrupt, with cytoskeletal regulators inDrosophilaepithelial tumorigenesis

“…Understanding the molecular events that occur during cooperative tumorigenesis is critical in order to develop therapeutics to combat cancer. The model organism, Drosophila melanogaster (vinegar fly), has proven to be an excellent model for the discovery of new tumorigenic genes and the dissection of their roles in tumour progression, and has proven relevance to human cancer ( Brumby and Richardson, 2005 ; Cheng et al, 2013 ; Gonzalez, 2013 ; Rudrapatna et al, 2012 ; Stefanatos and Vidal, 2011 ).…”