All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication. 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., 2010). JNK activity in somatic stem cells causes loss of tissue homeostasis in the aging Drosophila gut. (2017). doi: 10.1016/j.cell.2015.10.044, Yu, J., Zheng, Y., Dong, J., Klusza, S., Deng, W. M., and Pan, D. (2010). The regulation and functions of MAPK pathways in Drosophila. 6:e1001140. Given the heterogeneous nature of mammalian solid cancers, new strategies are being developed to decipher cancers at single-cell resolution. Nature 446, 325328. 64, 193196. These similarities with vertebrate hematopoiesis outline the utility of using fly models to elucidate the basic mechanisms of hematopoietic differentiation and homeostasis responsible for severe diseases, including leukemia. Rev. We have shown that we can use the reduction in female fecundity following oral exposure to chemotherapy drugs as a measure of chemotoxicity. (2006). The development of correct animal model also for these tumors will be essential to develop specific treatments that can tackle these different brain tumors in vivo. The physiological activation of the Hippo (HPO) kinase, (MST1/2 in human) (Harvey et al., 2003) consists in the phosphorylation of Warts (WTS), (LATS1/2 in human) (Genevet et al., 2010; Yu et al., 2010) and in the activation of the phosphorylated core complex, that includes Salvador (SAV in human) (Tapon et al., 2002) and Mob/MATS, that in turn, phosphorylate Yki (YAP/TAZ in humans) (Oh and Irvine, 2008). Nat. In Drosophila melanogaster, sexual adaptation shapes the chromosomal level genome organization, by which an embryo with the X:A ratio 0.5 develop into a male and an embryo with the X:A ratio 1.0, develop into the female. Epithelial polarity and proliferation control: links from the Drosophila neoplastic tumor suppressors. Centrosomal and non-centrosomal microtubule-organizing centers (MTOCs) in Drosophila melanogaster. Nature 457, 608611. Mech. The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. Extracellular vesicles and anti-cancer drug resistance. The adipose tissue produces pro-inflammatory cytokines including IL-6, IL-8, IFN, and TNF- among others (Scheller et al., 2011; Arango Duque and Descoteaux, 2014), and their over-production in fats from obese, activates the infiltration of macrophages into the adipose tissue inducing a low level of chronic inflammation or adipocyte tissue macrophage infiltration called ATM (Lafontan, 2014; Kuroda and Sakaue, 2017). doi: 10.1016/j.cell.2016.11.037, Lebestky, T., Jung, S. H., and Banerjee, U. Conclusion: Drosophila melanogaster has been one of the most fruitful models to study innate immunity. (2009). doi: 10.1016/j.cell.2011.02.013, Hariharan, I. K., and Bilder, D. (2006). 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., 2010). Genet. During organogenesis, the differentiation of the prostate's epithelium occurs along with that of stroma and depends on the complex coordination of many transcription factors and hormones that control the maturation of the quiescent organ (Toivanen and Shen, 2017). EMBO J. doi: 10.1016/j.ymeth.2014.01.020, Simon-Carrasco, L., Jimenez, G., Barbacid, M., and Drosten, M. (2018). At cellular level, the hyperproliferative status of cancer cells is mainly due to the activation of growth signals induced by proto-oncogenes (e.g., the RAS/RAF/MAPK axis), which function downstream of receptor signaling cascades, and are deregulated in 25% of human tumors (Samatar and Poulikakos, 2014). Moreover, activation of Wnt drives Myc upregulation in ISCs leading to non-autonomous upregulation of Upd3 in the ECs (Cordero et al., 2012a). Cell Stem Cell 8, 8495. A recent study demonstrated that the papillary carcinoma of the thyroid (PTC), also caused by another genomic mutations of RET gene, can be profitably studied using the accessory gland of Drosophila to delineate and understand the mechanisms that characterize PTC in the context of the whole animal, including the relationship between tumor and normal cells in an environment that mimics tumor of endocrine origin in humans (Levinson and Cagan, 2016). FEBS J. doi: 10.21873/anticanres.11366, Grewal, S. S. (2009). 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., 2010). Activation of Ras is considered a cancer distinctive trait both in Drosophila and humans, and it represents one of the strategies to model human cancer in flies. As a result, the cells of the tracheal branches over-proliferated to form tumors that ultimately killed the animals (Levine and Cagan, 2016). doi: 10.1016/j.celrep.2014.01.039, Pascual, J., Jacobs, J., Sansores-Garcia, L., Natarajan, M., Zeitlinger, J., Aerts, S., et al. doi: 10.1038/sj.onc.1208520, Schreiber-Agus, N., Stein, D., Chen, K., Goltz, J. S., Stevens, L., and DePinho, R. A. (2018). Sci. These tumor cells showed ectopic expression of Bnl (branchless), the Drosophila homolog of Fibroblast Growth Factors (FGFs,), and suffered from oxygen shortage (hypoxia). doi: 10.1016/j.tem.2012.11.002, Osman, D., Gobert, V., Ponthan, F., Heidenreich, O., Haenlin, M., and Waltzer, L. (2009). Reduced expression of Hugl-1, the human homologue of Drosophila tumour suppressor gene lgl, contributes to progression of colorectal cancer. Apoptotic cell death represents another physiological mechanism to maintain cellular homeostasis, and cancer cells have developed strategies to evade apoptosis, i.e., by increasing the activity of anti-apoptotic genes (Bcl-2, Bcl-xL, Bcl-w) and of pro-survival factors (Igf-1, Igf-2) or by downregulating the action of pro-apoptotic genes (Bax, PUMA, Bin) (Hanahan and Weinberg, 2011). Chromosomal instability is a process conserved also in Drosophila, and it was shown to contribute to the invasive behavior of epithelial cells, with a mechanism called compensatory proliferation activated to counteract CIN-induced cell death (Clemente-Ruiz et al., 2016; Benhra et al., 2018). Combined targeted treatment to eliminate tumorigenic cancer stem cells in human pancreatic cancer. Macrophage cytokines: involvement in immunity and infectious diseases. These larval organs are indeed morphologically and biochemically comparable to mammalian epithelia (Wodarz and Nathke, 2007). Drosophila melanogaster is a holometabolous insect, so it undergoes a full metamorphosis. 19, 623647. (2015). doi: 10.3171/2014.7.JNS131644, Ruivo, C. F., Adem, B., Silva, M., and Melo, S. A. Nat. Oncogene 24, 31003109. Biol. Genes Dev. 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. Annu. Cell Cycle 8, 32673273. Drug Discov. 5:a008904. Cell 168, 670691. 451, 548555. 18, 758770. Alterations in these proteins provoke continued cell proliferation, loss of differentiation and complete loss of tissue architecture, resulting in neoplastic overgrowth (Bilder, 2004; Grzeschik et al., 2010; Johnson and Halder, 2014). Natl. (2006). Mech. doi: 10.1101/cshperspect.a011254, Mortimer, N. T., and Moberg, K. H. (2013). Targeting de novo lipogenesis as a novel approach in anti-cancer therapy. Myc Function in Drosophila. The Genome Sequence of Drosophila melanogaster | Science [22] The eggs, which are about 0.5 mm long, hatch after 12-15 hours (at 25 C or 77 F). 9:e1001200. doi: 10.1016/j.cub.2015.12.043, Sun, G., and Irvine, K. D. (2013). ZD6474 suppresses oncogenic RET isoforms in a Drosophila model for type 2 multiple endocrine neoplasia syndromes and papillary thyroid carcinoma. Drug Dis. (2013). (2009). Other studies highlighted the role of hemocytes in the interplay between inflammation and cancer, i.e., using a classic cancer model that recapitulates the hallmarks of epithelial cancer cells (Rasv12/scribble/), it was shown that cancer cells induce hemocyte's recruitment and proliferation in vivo by activating JNK signaling to cause the expression of JAK/STAT cytokines (Pastor-Pareja et al., 2008). Cancer 118, 4351. During early embryogenesis, the sex chromosomal dimorphism, set irreversibly the transcriptional activity of Sex lethal (Sxl), that triggers the cascades of sex specific . Opin. Fly (Austin). Drosophila blood cells and their role in immune responses. Genet. Remarkably, the over-proliferation of the Apc / cells was rescued by lof mutation of Ras (Wang et al., 2013). In Drosophila cancer cells, the JNK pathway plays a dual role, by suppressing or promoting growth depending on the context (Brumby and Richardson, 2003; Uhlirova et al., 2005; Cordero et al., 2010). In particular PntP2, needs to be phosphorylated for its activation and is the principal activator of transcription downstream of many RTKs, and PntP1 is transcriptionally induced by MAPK (Shilo, 2014). 121, 339375. Loss of cell adhesion and cell polarity, with an increase of cell motility, are indeed characteristic early cancer traits. Tumorigenic properties of Drosophila epithelial cells mutant for lethal giant larvae. Front. Drosophila lung cancer models identify trametinib plus statin as candidate therapeutic. U.S.A. 102, 1312313128. Cell Stem Cell 3, 442455. Rev. (1998). Abnormalities in cell proliferation and apico-basal cell polarity are separable in Drosophila lgl mutant clones in the developing eye. (2011). doi: 10.1152/physrev.00030.2014, Gallant, P., Shiio, Y., Cheng, P. F., Parkhurst, S. M., and Eisenman, R. N. (1996). Body mass index and risk of renal cell cancer: a dose-response meta-analysis of published cohort studies. Phosphorylated Yki is sequestered and degraded in the cytoplasm, resulting in the inhibition of its nuclear transcriptional activity and oncogenic function (Harvey et al., 2013). 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., 2013). *Correspondence: Paola Bellosta, paola.bellosta@unitn.it, Model Organisms: A Precious Resource for Understanding of the Molecular Mechanisms Underlying Human Physiology and Disease, View all Cancer research needs in vivo investigations, and the use of model organisms contributes to answer this request. (2016). 72, 37093714. puckered encodes a phosphatase that mediates a feedback loop regulating JNK activity during dorsal closure in Drosophila.