Metabolic Adaptations in Cancer and the Host Using Drosophila Models and Advanced Tools

Abstract

Cancer is a multifactorial process involving genetic, epigenetic, physiological, and metabolic changes. The ability of tumours to regulate new reactive pathways is essential for their survival. A key aspect of this involves the decision-making process of cancer cells as they balance the exploitation of surrounding and distant tissues for their own benefit while avoiding the rapid destruction of the host. Nutrition plays a central role in these processes but is inherently limited. Understanding how tumour cells interact with non-tumoural tissues to acquire nutrients is crucial. In this review, we emphasise the utility of Drosophila melanogaster as a model organism for dissecting the complex oncogenic networks underlying these interactions. By studying various levels-from individual tumour cells to systemic markers-we can gain new insights into how cancer adapts and thrives. Moreover, developing innovative technologies, such as high-throughput methods and metabolic interventions, enhances our ability to explore how tumours adapt to different conditions. These technological advances allow us to explore tumour adaptations and open new opportunities for potential therapeutic strategies.

Keywords: anti-cancer drugs; cancer; diet; inter-organ communication; metabolism; metastasis; microenvironment; omics; systemic; technologies.

Figure 1

Internal metabolic adaptation in tumour cells. The diagram shows the tumour model genotypes and the processes involved. For aerobic glycolysis: Pvr^OE, Hipk^OE, and COX7a^RNAi Ras^V12/Dl^OE cancer models support the production of lactate via ImpL3, inhibiting the entrance of pyruvate into the mitochondria. In mitochondrial dysfunction: brat ^RNAi, pros^RNAi, aPKC-dp110^CAAX, Ras^V12 w/o lgl^−/−, N^OE, Hipck^OE, scrib^RNAi, and N^RNAi models generally require OxPhos to grow through mitochondrial dynamic changes as ETC and ROS production. Furthermore, other dynamic mitochondrial processes and ETC factors are necessary to keep ROS and NADH/NAD ratios. For harnessing amino acid and lipid storage: brat^RNAi, Ras^V12, nerfin-1¹⁵⁹, N^OE, Src42ACE JNK DN, bantam^OE rab^−/−, Ras^V12 scrib^−/−, Raf^gof, and EFGR^λ dp110^CAAX strains regulate the use of specific amino acids to fuel the TCA cycle, enhance pyrimidine synthesis, support ribogenesis, and drive cell proliferation, alongside the overexpression of amino acid transporters and increased fat storage.

Figure 2

Metabolic interaction between tumour cells and their microenvironment. The diagram displays the main processes between tumour and neighbouring cells, which rely on different larval and adult tumour models. Adult tumour brain by EGFR^λ dp110^CAAX mediates neuronal remodelling. Adult tumour gut by Ras^V12, Ras^V12 N^RNAi, Ras^Q13, and Raf^gof manage different processes such as tracheoneogenesis, nutrition microbiota interaction, and non-autonomous autophagy. Mutation in epithelial imaginal discs as wing (Ras^V12 scrib¹) and eye (Ras^V12 scrib^−/−, Ras^V12 lgl⁴, vps25^N55) support tumour expansion and haemocytes activation via disruption of BM, respectively.

Figure 3

Systemic metabolic interactions. The diagram shows the different systemic metabolic adaptations in larval and adult tumour models. Imaginal disc tumours originated by N^act, N^act Mef2^OE, Ras^V12 scrib^−/−, Ras^V12 dlg^RNAi, or Yki^act interact mainly with muscle tissues and fat body. The first one is to inhibit glycogen synthesis and lipogenesis, generate hyperglycaemia, and disrupt BM, provoking muscle wasting. In the fat body, there is an increase in fat reservoir and, by contrast, an increase in lipid mobilisation and the disruption of the basal membrane. In both tissues, nutrients are released by an increase in autophagy. Adult tumour tissues as gut by Yki^act or transplantation of imaginal discs Ras^V12scrib^−/− provoke muscle and fat body wasting via ImpL2 secretion. Furthermore, Yki^act induces lipid loss in the oenocytes, neuroendocrine secretion, and muscle dysfunction. Tumour induction in the eye imaginal disc generates cardiac dysfunction in the adult fly.