Drosophila melanogaster: A Model Organism to Study Cancer

Abstract

Cancer is a multistep disease driven by the activation of specific oncogenic pathways concomitantly with the loss of function of tumor suppressor genes that act as sentinels to control physiological growth. The conservation of most of these signaling pathways in Drosophila, and the ability to easily manipulate them genetically, has made the fruit fly a useful model organism to study cancer biology. In this review we outline the basic mechanisms and signaling pathways conserved between humans and flies responsible of inducing uncontrolled growth and cancer development. Second, we describe classic and novel Drosophila models used to study different cancers, with the objective to discuss their strengths and limitations on their use to identify signals driving growth cell autonomously and within organs, drug discovery and for therapeutic approaches.

Keywords: Drosophila cancer modeling; cancer biology; metabolism; oncogene; signaling; therapeutic approaches; tissue growth; tumor suppressor.

Figure 1

Graph representing the number of publications in PubMed found with the terms “Drosophila cancer model,” in the last 48 years.

Figure 2

Major pathways converging on uncontrolled growth in Drosophila epithelial cells. The signaling pathways outlined confer growth, migration and invasive capabilities to epithelial cells both in vertebrates and flies. Models that mimic the growth of epithelial cancer cells and their ability to undergo metastasis in Drosophila have been established by inducing the cooperation between oncogenes (RED) like the active form of Ras (Ras^V12) together with the loss of function of cell polarity genes (GREEN) (Brumby and Richardson, ; Pagliarini and Xu, 2003). Alteration of cell polarity with the downregulation of the SWH (Salvador-Hippo-Warts) pathway, together with Ras^V12, triggers downstream events, including activation of the MAPK signaling that stabilize Myc protein (Galletti et al., 2009) resulting in robust cellular growth. Activation of the JNK signaling, with the concomitant loss of cell polarity, induces metalloproteases (MMP-1) and confers to the epithelial cells the distinct characteristics of migration and invasion, hallmarks of tumor growth (Uhlirova et al., ; Igaki et al., ; Ma et al., 2017).

Figure 3

Cancer cells form branched and tubule-shaped structures (reproduced from Grifoni et al., 2015) with permission). (a) An imaginal wing disc bearing lgl⁴, Ras^V12 clones induced in a wild-type background. (b–b”) Magnifications of the central region squared in (a). Migrating tumor cells (GFP) are positive for the junctional marker aPKC (white) and secrete MMP1 (red). The reconstruction along the z-axis shown in the upper part of the magnified images reveals a tubule-shaped structure encircling a lumen, indicating these cells are forming tracheal-like structures.