Modelling Cooperative Tumorigenesis inDrosophila

Abstract

The development of human metastatic cancer is a multistep process, involving the acquisition of several genetic mutations, tumour heterogeneity, and interactions with the surrounding microenvironment. Due to the complexity of cancer development in mammals, simpler model organisms, such as the vinegar fly, Drosophila melanogaster, are being utilized to provide novel insights into the molecular mechanisms involved. In this review, we highlight recent advances in modelling tumorigenesis using the Drosophila model, focusing on the cooperation of oncogenes or tumour suppressors, and the interaction of mutant cells with the surrounding tissue in epithelial tumour initiation and progression.

Two-Faced: Roles of JNK Signalling During Tumourigenesis in the Drosophila Model

“…However, while activated Ras85D is known to block apoptosis (Bergmann et al, 1998;Kurada and White, 1998) and thus co-opt JNK signalling into promoting tissue growth (Figure 3), in other cases of cooperative tumourigenesis it is not clear how the apoptosis promoting role of JNK is halted. Examples of both such JNK-driven tumour types have recently been described elsewhere (reviewed in Richardson and Portela, 2018). We list some newly identified examples of JNK-driven tumourigenesis in various Drosophila tissues below.…”

StripandCkanegatively regulate JNK signalling duringDrosophilaspermatogenesis

“…TNF ligands in mammals are believed to be membrane-bound proteins, which can be cleaved, solubilised and then act in an autocrine or paracrine manner (Locksley et al, 2001;Smith et al, 1994). In Drosophila, it is unknown whether Egr behaves similarly or what the upstream regulators of its expression are, and the best-understood situation whereupon Egr expression is induced is after cell polarity loss (Igaki and Miura, 2014;Richardson and Portela, 2018). There, JNK signalling is activated in polaritydeficient cells via Egr secretion from various neighbouring cell types, and the mutant cells are eliminated via apoptosis.…”

Genome-wide RNAi screen for context-dependent tumor suppressors identified using in vivo models for neoplasia in Drosophila

“…Yki controls tissue growth by promoting cell proliferation and by concurrently inhibiting cell death through targets including Diap1, CycE and bantam miRNA [7, [36][37][38][39]. The central role of the Hippo pathway as an integrator of other growth-related signals may also contribute to the abundance of tumor suppressors associated with Yki-driven growth [1,2,26]. Mis-regulation of this pathway also contributes to tumor formation in mouse models [40].…”

“…Genetic approaches using Drosophila models of oncogene cooperation have also been used to identify genes that act together with known cancer drivers in tumor formation [8,9,[18][19][20] [21,22] [2, 23]. The simplicity of the Drosophila genome, coupled with the ease of large-scale genetic screens and the high degree of conservation of major signaling pathways with humans, make Drosophila an interesting model to identify novel cancer genes and to study the cellular and molecular mechanisms that underlie tumor formation in vivo (reviewed in [24][25][26][27]).…”