Drosophila is often fed complex solid diets based on yeast, corn, and agar. There are also so-called holidic diets available that are defined in terms of their amino acid, fatty acid, carbohydrate, vitamin, mineral, and trace element compositions. Feed intake, body composition, locomotor activity, intestinal barrier function, microbiota, cognition, fertility, aging, and life span can be systematically determined in Drosophila in response to dietary factors.
Furthermore, diet-induced pathophysiological mechanisms including inflammation and stress responses may be evaluated in the fly under defined experimental conditions. Here, we critically evaluate Drosophila melanogaster as a versatile model organism in experimental food and nutrition research, review the corresponding data in the literature, and make suggestions for future directions of research.
Food Chem. More by Stefanie Staats. More by Anika E. More by Gerald Rimbach. Cite this: J. Article Views Altmetric -. Citations Cited By. This article is cited by 27 publications. Kaufman , Y. Seidler , H. Bailey , L. Whitacre , F. Bargo , K. Rimbach , G. Pighetti , I.
Ipharraguerre , A. A postbiotic from Aspergillus oryzae attenuates the impact of heat stress in ectothermic and endothermic organisms. Red ginseng has stronger anti-aging effects compared to ginseng possibly due to its regulation of oxidative stress and the gut microbiota.
Phytomedicine , 93 , International Journal of Molecular Sciences , 22 21 , Drosophila as an emerging model organism for studies of food-derived antioxidants. Food Research International , , In vertebrate tumors, the fusion of AML1 with the repressor ETO inhibits the differentiation of the multilineage progenitor cells, while their proliferation is activated, leading to AML1.
Interestingly, AML1 fused with ETO in Drosophila also causes the inhibition of hematopoietic cell differentiation, confirming that the fly is a good genetic model to study the mechanisms that drive leukemia in humans Osman et al. Myeloproliferative neoplasms MPNs have also been reproduced in the fly through gain-of-function mutations in the JAK pathway, finding a role for the downstream effector of the SWH pathway Yki in priming the expansion of Drosophila blood cells, which undergo malignant behavior following JAK activation Anderson et al.
The inflammatory response of cancer cells has been attributed to a response of the immune system to eradicate the tumor, but it can also be seen as a way to provide growth and survival, as inflammation contributes to genomic instability by releasing cytokines and through production of reactive oxygen species ROS that may induce genetic and genomic alterations Negrini et al.
Normal cells detect and repair DNA damage, ensuring the maintenance of the correct number of chromosomes and tissue homeostasis, instead often cancer cells have increased mutation-rates leading to high chromosomal instability CIN that triggers aneuploidy and advances tumorigenesis Negrini et al. Thus these opposite signaling pathways activated by TNF signals depend on the adaptor complexes recruited by the receptors and by the cellular context, and they may create a problem for the development of therapeutic strategies that target TNF signaling in tumors Ham et al.
Other studies highlighted the role of hemocytes in the interplay between inflammation and cancer, i. Using a similar model it was shown that Egr expression was higher in the hemocytes derived from cancer animals, and that its activity was necessary to stimulate invasive migration of tumor cells Cordero et al. Work using allograft transplantation experiments, identify also a function for the hemocytes in tumor initiation, that is independent on Eiger, but relays rather on the activation by external stimuli i.
In summary, all these data suggest the existence of conserved mechanisms between the immune and tumor cells in flies that may recapitulate some of the most evolutionary conserved aspects described in cancer cells.
In tumor biology, evidences highlight the relevance of lipid metabolism in influencing tumor growth Katheder and Rusten, ; Weber et al. In this context, a recent role was identified for adipose triglyceride lipase ATGL whereby it hydrolyzes triacylglycerols into fatty acids FAs that may act as signaling molecules to induce growth both cell autonomously and in neighboring cells Walther and Farese, The contribution of ATGL to cancer growth is controversial, indeed several studies showed that its depletion reduced proliferation in colorectal cancer cells and in non-small-cell lung carcinoma Ou et al.
On the contrary, lack of ATGL favored pulmonary neoplasia in mice, and in few human tumors ATGL expression was found reduced highlighting the complex role of lipids in tumorigenesis Al-Zoughbi et al. Recent work associated the mechanism of lypolysis with the induction of autophagy, a mechanism used by the cells to re-cycle part of their cytoplasm or cellular content to survive when nutrients are reduced Dall'Armi et al.
The relevance in cancer of the link between lipids and autophagy was shown when ATGL-mediated lipolysis in a peritumoral area, increased autophagy and tumor survival using a non-autonomous mechanisms Martinez-Outschoorn et al.
Interestingly, we observed that Myc in Drosophila induced autophagy in the fat body and this was enough to enhance survival of the whole animals upon starvation Parisi et al.
We linked this effect with the ability of Myc to increase desat1, a Stearoyl-CoA desaturase-1 SCD1 key enzyme in the synthesis of lipids, that we found co-expressed with Myc in human prostatic tumors Paiardi et al. Metabolic disorders and obesity are associated with cardiovascular disease and type II diabetes T2D , however numerous cohort studies reported that overweight people are more likely to develop certain types of cancer including endometrial, breast, liver, and ovarian cancer Cancer, ; Chen et al.
Obese people have often increased levels of circulating hormones like insulin that has been associated to higher levels of IGF-1 in colon, kidney, prostate and endometrial cancer Roberts et al.
Another hormone, leptin, a cytokine produced by the adipocytes to control satiety in a signaling circuit of the brain, has also been found up-regulated in tissues from obese people, particularly in women post-menopause, and increased levels of leptin have been associated with higher incidence of breast and other tumors Ray, This low level of inflammation increases the levels of ROS and induces DNA and protein damage that may increase the risk of cancer Lafontan, ; Mraz and Haluzik, The role of the inflammatory response to combat infection and tissue injury, through the activation of the immune cells, is conserved also in Drosophila's circulating hemocytes Lemaitre and Hoffmann, , where most of the signals activated in the fat body results also in ROS production Dionne, ; Vlisidou and Wood, Indeed, we showed, using a genetic model that harbors an inflammation state in the fat body of larvae that mimic ATM, that reduction of ROS, using exogenous anti-oxidants components like flavonoids and anthiocianins, decreased hemocyte's migration and JNK activation in the cells of fat body Valenza et al.
Cancer stem cells CSCs have more features than tissue stem cells because they are able to initiate the tumor growth and fuel its maintenance and metastasis Malanchi et al. In addition, CSCs are highly resistant to conventional therapy, both radiation and chemotherapy, and they are responsible for the recurrence of disease Mueller et al. Since the mechanisms underlying the ability of stem cells to support cancer progression are still unclear, Drosophila is convenient to use as it provides many tools for genetic and molecular investigations.
Adult stem cells are required for tissue homeostasis and repair after injury and in adult flies, populations of stem cells are present in the posterior midgut, testis, and ovarian follicle rendering it again a good system to dissect these stem cell programs Hou and Singh, Drosophila was used to better understand the functions of the centrosome and microtubule-organizing center MTOC in the division of stem cells Tillery et al.
Drosophila and mammalian stem cells are similar and they are regulated by homologous signals corroborating the use of the fly in this field of tumor biology. CSCs can arise from normal stem cells whose long lifespan favors the accumulation of genetic mutations responsible for the malignant phenotype.
The progression from normal progenitors to stem-like cancer cells was first explored in leukemia, although nowadays we know that several solid tumors such as brain, breast, lung and colon cancer originate from cells with stem features Krivtsov et al.
Several Drosophila models of stem cell tumors are now available, and a drug screening was successfully carried out highlighting several compounds active on the signaling promoting cancer growth Markstein et al. Therapeutic drug discovery requires chemical screening, a procedure allowing for the identification of potential new drugs.
The spread of sequencing, automation, and miniaturization has made High Throughput Screening HTS the leading contributor to early-stage drug discovery. HTS consists of random screening of chemicals to find an affinity for a specific protein or biological activity characteristic of a disorder. Once identified in vitro , the compounds need to be validated in vivo to assess efficacy and toxicity during a long and expensive period of drug development.
The high throughput assays depend on the existence of a specific target, assuming an in depth understanding of a disease that is not always available. Phenotype screening is an eligible option when the knowledge about the mechanisms underlying a disease process is not well defined.
It is a process by which small molecules are screened for their effect on the phenotype in cells, tissue or whole animals, where a more physiological environment better describes the pharmacokinetics and toxicological effects of a drug.
The great availability of genetic tools and the low cost of maintenance makes the fruit fly an ideal to model to study human diseases including cancer, in fact the fly has considerably contributed to understand tumor biology.
Chemical screens have been successfully performed in Drosophila for several disorders affecting the central nervous system, kidney and metabolism Whitworth et al.
The availability of Drosophila models for multiple cancer types makes pharmacological screens possible against several drugs that aim to restrict proliferation and metastasis. The identification of anticancer compounds is possible using the adult fly, but also larvae, embryos and cells.
The combined effect of anti-cancer drugs with radiation has been investigated in Drosophila larvae, producing similar findings to those observed in human cancer cells Edwards et al.
Moreover, Drosophila avatars, consisting of patient-specific tumors modeled in transgenic flies, are very promising for personalized medicine. Drosophila and other small model organisms are helpful to quickly analyze the mode of action of several active compounds in vivo , nevertheless mammalian models are indispensable in the successive phase of drug development to define important pharmacokinetic parameters such as absorption, distribution and metabolism.
The communication between tumor cells and their microenvironment is largely implicated in neoplastic growth, hence the substantial difficulty to recapitulate the features of malignant transformation in cellular systems.
Cancer research needs in vivo investigations, and the use of model organisms contributes to answer this request. In this review we described most relevant approaches in Drosophila , used to explore cancer mechanisms and therapeutics that contribute to our understanding on tumor initiation and progression.
In spite of some limitations, because of the anatomical differences between flies and humans, the use of Drosophila 's cancer models has been fundamental to understand some basic processes that regulate human cancers, such as the competitiveness of cancer stem cells CSCs , the importance of tumor microenvironment, cancer cachexia, drug resistance and tumor-associated vasculogenesis, which was recently found to be functionally conserved in fly's cancer.
Additional cancer hallmarks such as genomic instability, resistance to cell death, cell metabolism reprogramming, tumor-promoting inflammation and evasion from the immune system, have been studied and extensively characterized in Drosophila. Finally, although the evolutionary difference between Drosophila and humans certainly represents a restriction to the use of the fruit fly in drug discovery and development, phenotypic screenings have proven relevant to identify potential drugs that would elude the classic screens in the absence of targets.
Drosophila is also offering a significant contribution to the investigation of organotypic cancers, since despite the evident differences at the macroscopic level, organ cells and functional units are usually well conserved at the biochemical and structural levels respectively. This conservation allowed to develop thyroid, lung, prostate, gut, brain and blood cancer models starting from the most characteristic genetic lesions found in the same human cancers.
These models, as described in the review, are greatly helping in dissecting the contribution of specific molecular pathways to the final cancer phenotype. Given the heterogeneous nature of mammalian solid cancers, new strategies are being developed to decipher cancers at single-cell resolution.
The international Drosophila community has always been engaged in the development of novel, sophisticated genetic tools, which allowed in the last 30 years to revolutionate functional gene analysis. For this reason, we anticipate that the use of the fruit fly will move fast into the field of precision medicine, contributing to seminal findings in this new era of cancer research. All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. We apologize to colleagues whose work was not cited in this manuscript due to space limitations. We thank all members of Bellosta's and Grifoni's laboratories and Sheri Zola for their comments on the review. Aavikko, M. Loss of SUFU function in familial multiple meningioma.
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