There is a large gap between the deep understanding of mechanisms driving tumour growth and the reasons why patients ultimately die of cancer. It is now appreciated that interactions between the tumour and surrounding non-tumour (sometimes referred to as host) cells play critical roles in mortality as well as tumour progression, but much remains unknown about the underlying molecular mechanisms, especially those that act beyond the tumour microenvironment. Drosophila has a track record of high-impact discoveries about cell-autonomous growth regulation, and is well suited to now probe mysteries of tumour – host interactions. Here, we review current knowledge about how fly tumours interact with microenvironmental stroma, circulating innate immune cells and distant organs to influence disease progression. We also discuss reciprocal regulation between tumours and host physiology, with a particular focus on paraneoplasias. The fly’s simplicity along with the ability to study lethality directly provide an opportunity to shed new light on how cancer actually kills.
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Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).
Pelosof, L. C. & Gerber, D. E. Paraneoplastic syndromes: an approach to diagnosis and treatment. Mayo Clin. Proc. 85, 838–854 (2010).
Fearon, K. C. H., Glass, D. J. & Guttridge, D. C. Cancer cachexia: mediators, signaling, and metabolic pathways. Cell Metab. 16, 153–166 (2012).
Tisdale, M. J. Mechanisms of cancer cachexia. Physiol. Rev. 89, 381–410 (2009).
Argilés, J. M., Stemmler, B., López-Soriano, F. J. & Busquets, S. Inter-tissue communication in cancer cachexia. Nat. Rev. Endocrinol. 15, 9–20 (2018).
Enya, S., Kawakami, K., Suzuki, Y. & Kawaoka, S. A novel zebrafish intestinal tumor model reveals a role for cyp7a1-dependent tumor-liver crosstalk in causing adverse effects on the host. Dis. Model. Mech. 11, dmm032383 (2018).
Cagan, R. L., Zon, L. I. & White, R. M. Modeling cancer with flies and fish. Dev.Cell 49, 317–324 (2019).
Bilder, D. & Irvine, K. D. Taking stock of the Drosophila research ecosystem. Genetics 206, 1227–1236 (2017).
Bellen, H. J., Wangler, M. F. & Yamamoto, S. The fruit fly at the interface of diagnosis and pathogenic mechanisms of rare and common human diseases. Hum. Mol. Genet. 28, R207–R214 (2019).
Hu, Y. et al. An integrative approach to ortholog prediction for disease-focused and other functional studies. BMC Bioinforma. 12, 357 (2011).
Bailey, M. H. et al. Comprehensive characterization of cancer driver genes and mutations. Cell 173, 371–385.e18 (2018).
Bilder, D. Epithelial polarity and growth control: links from the Drosophila neoplastic tumor suppressors. Genes Dev. 18, 1909–1925 (2004).
Gonzalez, C. Drosophila melanogaster: a model and a tool to investigate malignancy and identify new therapeutics. Nat. Rev. Cancer 13, 172–183 (2013).
Chatterjee, D. & Deng, W. M. Drosophila model in cancer: an introduction. Adv. Exp. Med. Biol. 1167, 1–14 (2019).
Mirzoyan, Z. et al. Drosophila melanogaster: a model organism to study cancer. Front. Genet. 10, 51 (2019).
Gateff, E. & Schneiderman, H. A. Neoplasms in mutant and cultured wild-type tissues of Drosophila. Natl Cancer Inst. Monogr. 31, 365–397 (1969). This landmark report of fly tumours and tumour suppressor genes includes impacts on transplanted hosts.
Rossi, F. & Gonzalez, C. Studying tumor growth in Drosophila using the tissue allograft method. Nat. Protoc. 10, 1525–1534 (2015). This paper presents an excellent and straightforward protocol for fly tumour transplantation.
Pagliarini, R. A. & Xu, T. A genetic screen in Drosophila for metastatic behavior. Science 302, 1227–1231 (2003). This article documents tissue invasion and dispersion by a Ras-stimulated cooperative neoplastic tumour.
Egeblad, M., Nakasone, E. S. & Werb, Z. Tumors as organs: complex tissues that interface with the entire organism. Dev. Cell 18, 884–901 (2010).
Maman, S. & Witz, I. P. A history of exploring cancer in context. Nat. Rev. Cancer 18, 359–376 (2018).
Hanahan, D. & Coussens, L. M. Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell 21, 309–322 (2012).
Binnewies, M. et al. Understanding the tumor immune microenvironment (TIME) for effective therapy. Nat. Med. 24, 541–550 (2018).
Patel, P. H., Dutta, D. & Edgar, B. A. Niche appropriation by Drosophila intestinal stem cell tumours. Nat. Cell Biol. 17, 1182–1192 (2015).
Cordero, J. B., Stefanatos, R. K., Myant, K., Vidal, M. & Sansom, O. J. Non-autonomous crosstalk between the Jak/Stat and Egfr pathways mediates Apc1-driven intestinal stem cell hyperplasia in the Drosophila adult midgut. Development 139, 4524–4535 (2012). Together with Patel et al. (2015), this paper shows how tumours can induce a damage response from a wild-type stem cell niche to stimulate their growth.
Vaccari, T. & Bilder, D. The Drosophila tumor suppressor vps25 prevents nonautonomous overproliferation by regulating notch trafficking. Dev. Cell 9, 687–698 (2005).
Moberg, K. H., Schelble, S., Burdick, S. K. & Hariharan, I. K. Mutations in erupted, the Drosophila ortholog of mammalian tumor susceptibility gene 101, elicit non-cell-autonomous overgrowth. Dev. Cell 9, 699–710 (2005).
Classen, A. K., Bunker, B. D., Harvey, K. F., Vaccari, T. & Bilder, D. A tumor suppressor activity of Drosophila Polycomb genes mediated by JAK–STAT signaling. Nat. Genet. 41, 1150–1155 (2009).
Martinez, A. M. et al. Polyhomeotic has a tumor suppressor activity mediated by repression of Notch signaling. Nat. Genet. 41, 1076–1082 (2009).
Loubiere, V. et al. Coordinate redeployment of PRC1 proteins suppresses tumor formation during Drosophila development. Nat. Genet. 48, 1436–1442 (2016).
Baker, N. E. Emerging mechanisms of cell competition. Nat. Rev. Genet. 21, 683–697 (2020).
Madan, E., Gogna, R. & Moreno, E. Cell competition in development: information from flies and vertebrates. Curr. Opin. Cell Biol. 55, 150–157 (2018).
Nagata, R. & Igaki, T. Cell competition: emerging mechanisms to eliminate neighbors. Dev. Growth Differ. 60, 522–530 (2018).
Johnston, L. A. Socializing with MYC: cell competition in development and as a model for premalignant cancer. Cold Spring Harb. Perspect. Med. 4, a014274 (2014).
Yamamoto, M., Ohsawa, S., Kunimasa, K. & Igaki, T. The ligand Sas and its receptor PTP10D drive tumour-suppressive cell competition. Nature 542, 246–250 (2017).
Cordero, J. B. et al. Oncogenic ras diverts a host TNF tumor suppressor activity into tumor promoter. Dev. Cell 18, 999–1011 (2010).
Igaki, T., Pastor-Pareja, J. C., Aonuma, H., Miura, M. & Xu, T. Intrinsic tumor suppression and epithelial maintenance by endocytic activation of Eiger/TNF signaling in Drosophila. Dev. Cell 16, 458–465 (2009).
Chen, C.-L. L., Schroeder, M. C., Kango-Singh, M., Tao, C. & Halder, G. Tumor suppression by cell competition through regulation of the Hippo pathway. Proc. Natl Acad. Sci. USA 109, 484–489 (2012).
Herranz, H., Weng, R. & Cohen, S. M. Crosstalk between epithelial and mesenchymal tissues in tumorigenesis and imaginal disc development. Curr. Biol. 24, 1476–1484 (2014).
Boukhatmi, H., Martins, T., Pillidge, Z., Kamenova, T. & Bray, S. Notch mediates inter-tissue communication to promote tumorigenesis. Curr. Biol. 30, 1809–1820.e4 (2020).
Muzzopappa, M., Murcia, L. & Milan, M. Feedback amplification loop drives malignant growth in epithelial tissues. Proc. Natl Acad. Sci. USA 114, E7291–E7300 (2017).
Hayashi, S. & Kondo, T. Development and function of the Drosophila tracheal system. Genetics 209, 367–380 (2018).
Kotini, M. P., Mäe, M. A., Belting, H. G., Betsholtz, C. & Affolter, M. Sprouting and anastomosis in the Drosophila trachea and the vertebrate vasculature: similarities and differences in cell behaviour. Vasc. Pharmacol. 112, 8–16 (2019).
Grifoni, D., Sollazzo, M., Fontana, E., Froldi, F. & Pession, A. Multiple strategies of oxygen supply in Drosophila malignancies identify tracheogenesis as a novel cancer hallmark. Sci. Rep. 5, 9061 (2015). This paper describes the host tracheal response to fly tumours, and vascular mimicry of fly tumour cells.
Hirabayashi, S., Baranski, T. J. & Cagan, R. L. Transformed Drosophila cells evade diet-mediated insulin resistance through wingless signaling. Cell 154, 664–675 (2013). This work examines the interface of diet and tumour genotype on pathways driving oncogenic progression.
Mishra-Gorur, K. et al. Spz/Toll-6 signal guides organotropic metastasis in Drosophila. Dis. Model. Mech. 12, dmm039727 (2019).
Bangi, E., Murgia, C., Teague, A. G. S., Sansom, O. J. & Cagan, R. L. Functional exploration of colorectal cancer genomes using Drosophila. Nat. Commun. 7, 13615 (2016).
Calleja, M., Morata, G. & Casanova, J. Tumorigenic properties of Drosophila epithelial cells mutant for lethal giant larvae. Dev. Dyn. 245, 834–843 (2016).
Hendrix, M. J. C., Seftor, E. A., Hess, A. R. & Seftor, R. E. B. Vasculogenic mimicry and tumour-cell plasticity: lessons from melanoma. Nat. Rev. Cancer 3, 411–421 (2003).
Potente, M., Gerhardt, H. & Carmeliet, P. Basic and therapeutic aspects of angiogenesis. Cell 146, 873–887 (2011).
Noy, R. & Pollard, J. W. Tumor-associated macrophages: from mechanisms to therapy. Immunity 41, 49–61 (2014).
Lemaitre, B., Hoffmann, J. & Hoffman, J. The host defense of Drosophila melanogaster. Annu. Rev. Immunol. 25, 697–743 (2007).
Banerjee, U., Girard, J. R., Goins, L. M. & Spratford, C. M. Drosophila as a genetic model for hematopoiesis. Genetics 211, 367–417 (2019).
Gold, K. S. & Brückner, K. Macrophages and cellular immunity in Drosophila melanogaster. Semin. Immunol. 27, 357–368 (2015).
Sanchez Bosch, P. et al. Adult Drosophila lack hematopoiesis but rely on a blood cell reservoir at the respiratory epithelia to relay infection signals to surrounding tissues. Dev. Cell 51, 787–803.e5 (2019).
Theopold, U., Krautz, R. & Dushay, M. S. The Drosophila clotting system and its messages for mammals. Dev. Comp. Immunol. 42, 42–46 (2014).
Pastor-Pareja, J. C., Wu, M. & Xu, T. An innate immune response of blood cells to tumors and tissue damage in Drosophila. Dis. Model. Mech. 1, 144–154 (2008). This paper is a pioneering study of innate immune response to fly tumours.
Parisi, F., Stefanatos, R. K., Strathdee, K., Yu, Y. & Vidal, M. Transformed epithelia trigger non-tissue-autonomous tumor suppressor response by adipocytes via activation of Toll and Eiger/TNF signaling. Cell Rep. 6, 855–867 (2014). This paper identifies an inter-tissue communication network between fly tumours, macrophages and adipose tissue.
Parvy, J.-P. et al. The antimicrobial peptide defensin cooperates with tumour necrosis factor to drive tumour cell death in Drosophila. eLife 8, e45061 (2019). This paper reports a mechanism by which cellular and humoral innate immune systems cooperate to limit fly tumour growth.
Tornesello, A. L., Borrelli, A., Buonaguro, L., Buonaguro, F. M. & Tornesello, M. L. Antimicrobial peptides as anticancer agents: functional properties and biological activities. Molecules 25, 2850 (2020).
Marcus, A. et al. in Advances in Immunology Vol. 122 91–128 (Academic, 2014).
La Marca, J. E. & Richardson, H. E. Two-faced: roles of JNK signalling during tumourigenesis in the drosophila model. Front. Cell Dev. Biol. 8, 42 (2020).
Diwanji, N. & Bergmann, A. Basement membrane damage by ROS- and JNK-mediated Mmp2 activation drives macrophage recruitment to overgrown tissue. Nat. Commun. 11, 3631 (2020).
Pérez, E., Lindblad, J. L. & Bergmann, A. Tumor-promoting function of apoptotic caspases by an amplification loop involving ROS, macrophages and JNK in Drosophila. eLife 6, e26747 (2017).
Kotsafti, A., Scarpa, M., Castagliuolo, I. & Scarpa, M. Reactive oxygen species and antitumor immunity — from surveillance to evasion. Cancers 12, 1–16 (2020).
Boccaccio, C. & Comoglio, P. M. Genetic link between cancer and thrombosis. J. Clin. Oncol. 27, 4827–4833 (2009).
Thuma, L., Carter, D., Weavers, H. & Martin, P. Drosophila immune cells extravasate from vessels to wounds using Tre1 GPCR and Rho signaling. J. Cell Biol. 217, 3045–3056 (2018).
Stuelten, C. H., Parent, C. A. & Montell, D. J. Cell motility in cancer invasion and metastasis: insights from simple model organisms. Nat. Rev. Cancer 18, 296–312 (2018).
Stefanatos, R. K. A. & Vidal, M. Tumor invasion and metastasis in Drosophila: a bold past, a bright future. J. Genet. Genomics 38, 431–438 (2011).
Gateff, E. & Schneiderman, H. A. Developmental capacities of benign and malignant neoplasms of Drosophila. W. Roux’ Archiv f. Entwicklungsmechanik 176, 23–65 (1974).
Uhlirova, M. & Bohmann, D. JNK- and Fos-regulated Mmp1 expression cooperates with Ras to induce invasive tumors in Drosophila. EMBO J. 25, 5294–5304 (2006).
Srivastava, A., Pastor-Pareja, J. C., Igaki, T., Pagliarini, R. & Xu, T. Basement membrane remodeling is essential for Drosophila disc eversion and tumor invasion. Proc. Natl Acad. Sci. USA 104, 2721–2726 (2007).
Woodhouse, E. C. et al. Drosophila screening model for metastasis: Semaphorin 5c is required for l(2)gl cancer phenotype. Proc. Natl Acad. Sci. USA 100, 11463–11468 (2003).
Beaucher, M., Hersperger, E., Page-McCaw, A. & Shearn, A. Metastatic ability of Drosophila tumors depends on MMP activity. Dev. Biol. 303, 625–634 (2007).
Stickel, S. & Su, T. T. Oncogenic mutations produce similar phenotypes in Drosophila tissues of diverse origins. Biol. Open 3, 201–208 (2014).
Lee, J., Cabrera, A. J. H., Nguyen, C. M. T. & Kwon, Y. V. Dissemination of RasV12-transformed cells requires the mechanosensitive channel Piezo. Nat. Commun. 11, 3568 (2020).
Campbell, K. et al. Collective cell migration and metastases induced by an epithelial-to-mesenchymal transition in Drosophila intestinal tumors. Nat. Commun. 10, 2311 (2019). This paper is the most clear documentation to date of metastatic-like behaviour of fly tumour cells.
Martin, J. L. et al. Long-term live imaging of the Drosophila adult midgut reveals real-time dynamics of division, differentiation and loss. eLife 7, e36248 (2018).
Jaramillo Koyama, L. A. et al. Bellymount enables longitudinal, intravital imaging of abdominal organs and the gut microbiota in adult Drosophila. PLoS Biol. 18, e3000567 (2020).
McAllister, S. S. & Weinberg, R. A. The tumour-induced systemic environment as a critical regulator of cancer progression and metastasis. Nat. Cell Biol. 16, 717–727 (2014).
Figueroa-Clarevega, A. & Bilder, D. Malignant Drosophila tumors interrupt insulin signaling to induce cachexia-like wasting. Dev. Cell 33, 47–55 (2015).
Kwon, Y. et al. Systemic organ wasting induced by localized expression of the secreted insulin/IGF antagonist ImpL2. Dev. Cell 33, 36–46 (2015). Together with Figueroa-Clarevega and Bilder (2015), this paper demonstrates that fly tumours induce cachexia and identifies the underlying mechanism.
Honegger, B. et al. Imp-L2, a putative homolog of vertebrate IGF-binding protein 7, counteracts insulin signaling in Drosophila and is essential for starvation resistance. J. Biol. 7, 10 (2008).
Song, W. et al. Tumor-derived ligands trigger tumor growth and host wasting via differential MEK activation. Dev. Cell 48, 277–286 (2019).
Newton, H. et al. Systemic muscle wasting and coordinated tumour response drive tumourigenesis. Nat. Commun. 11, 4653 (2020).
Dev, R., Bruera, E. & Dalal, S. Insulin resistance and body composition in cancer patients. Ann. Oncol. 29, ii18–ii26 (2018).
Wagner, E. F. & Petruzzelli, M. Cancer metabolism: a waste of insulin interference. Nature 521, 430–431 (2015).
Huang, X. Y. et al. Pancreatic cancer cell-derived IGFBP-3 contributes to muscle wasting. J. Exp. Clin. Cancer Res. 35, 46 (2016).
Penna, F. et al. Muscle wasting and impaired myogenesis in tumor bearing mice are prevented by ERK inhibition. PLoS ONE 5, e13604 (2010).
Tisdale, M. J. Cancer anorexia and cachexia. Nutrition 17, 438–442 (2001).
Patra, S. K. & Arora, S. Integrative role of neuropeptides and cytokines in cancer anorexia–cachexia syndrome. Clinica Chim. Acta 413, 1025–1034 (2012).
Yeom, E. et al. Tumour-derived Dilp8/INSL3 induces cancer anorexia by regulating feeding neuropeptides via Lgr3/8 in the brain. Nat. Cell Biol. 23, 172–183 (2021). This work describes an evolutionarily conserved pathway by which chronic Hippo signalling can alter host feeding behaviour.
Vallejo, D. M., Juarez-Carreno, S., Bolivar, J., Morante, J. & Dominguez, M. A brain circuit that synchronizes growth and maturation revealed through Dilp8 binding to Lgr3. Science 350, aac6767 (2015).
Colombani, J. et al. Drosophila Lgr3 couples organ growth with maturation and ensures developmental stability. Curr. Biol. 25, 2723–2729 (2015).
Garelli, A. et al. Dilp8 requires the neuronal relaxin receptor Lgr3 to couple growth to developmental timing. Nat. Commun. 6, 8732 (2015).
Jaszczak, J. S., Wolpe, J. B., Bhandari, R., Jaszczak, R. G. & Halme, A. Growth coordination during Drosophila melanogaster imaginal disc regeneration is mediated by signaling through the relaxin receptor Lgr3 in the prothoracic gland. Genetics 204, 703–709 (2016).
Poillet-Perez, L. & White, E. Role of tumor and host autophagy in cancer metabolism. Genes. Dev. 33, 610–619 (2019).
Katheder, N. S. et al. Microenvironmental autophagy promotes tumour growth. Nature 541, 417–420 (2017). This article shows how fly tumour growth is fuelled by induction of autophagy in host cells.
Rybstein, M. D., Pedro, B. S., JM, Kroemer, G. & Galluzzi, L. The autophagic network and cancer. Nat. Cell Biol. 20, 243–251 (2018).
Hadorn, E. An accelerating effect of normal ‘ring-glands’ on puparium-formation in lethal larvae of Drosophila melanogaster. Proc. Natl Acad. Sci. USA 23, 478–484 (1937).
Bridges, C. B. & Brehme, K. S. The Mutants of Drosophila melanogaster (Carnegie Institution, 1944).
Gateff, E. & Schneiderman, H. A. Developmental studies of a new mutant of Drosophila melanogaster: lethal malignant brain tumor (I(2)gl4). Am. Zool. 7, 760 (1967).
Menut, L. et al. A mosaic genetic screen for Drosophila neoplastic tumor suppressor genes based on defective pupation. Genetics 177, 1667–1677 (2007). This paper is an early demonstration that diverse fly tumours are sufficient to non-autonomously induce systemic defects in host maturation.
Caussinus, E. & Gonzalez, C. Induction of tumor growth by altered stem-cell asymmetric division in Drosophila melanogaster. Nat. Genet. 37, 1125–1129 (2005).
Garelli, A., Gontijo, A. M., Miguela, V., Caparros, E. & Dominguez, M. Imaginal discs secrete insulin-like peptide 8 to mediate plasticity of growth and maturation. Science 336, 579–582 (2012).
Colombani, J., Andersen, D. S. & Leopold, P. Secreted peptide Dilp8 coordinates Drosophila tissue growth with developmental timing. Science 336, 582–585 (2012). Together with Garelli et al. (2012), this paper identifies a signal from growing organs, damaged tissues and tumours that acts on the fly brain to prevent pupation.
Bunker, B. D., Nellimoottil, T. T., Boileau, R. M., Classen, A. K. & Bilder, D. The transcriptional response to tumorigenic polarity loss in Drosophila. eLife 4, e03189 (2015).
Romão, D., Muzzopappa, M., Barrio, L. & Milán, M. The Upd3 cytokine couples inflammation to maturation defects in Drosophila. Curr. Biol. 31, 1780–1787 (2021).
Cohen, E., Sawyer, J. K., Peterson, N. G., Dow, J. A. T. & Fox, D. T. Physiology, development, and disease modeling in the Drosophila excretory system. Genetics 214, 235–264 (2020).
Saxena, A. et al. Epidermal growth factor signalling controls myosin II planar polarity to orchestrate convergent extension movements during Drosophila tubulogenesis. PLoS Biol. 12, e1002013 (2014).
Denholm, B. et al. The tiptop/teashirt genes regulate cell differentiation and renal physiology in Drosophila. Development 140, 1100–1110 (2013).
Cognigni, P., Bailey, A. P. & Miguel-Aliaga, I. Enteric neurons and systemic signals couple nutritional and reproductive status with intestinal homeostasis. Cell Metab. 13, 92–104 (2011).
Cabrero, P. et al. Chloride channels in stellate cells are essential for uniquely high secretion rates in neuropeptidestimulated Drosophila diuresis. Proc. Natl Acad. Sci. USA 111, 14301–14306 (2014).
Deng, T., Lyon, C. J., Bergin, S., Caligiuri, M. A. & Hsueh, W. A. Obesity, inflammation, and cancer. Annu. Rev. Pathol. Mech. Dis. 11, 421–449 (2016).
Nowak, K., Gupta, A. & Stocker, H. FoxO restricts growth and differentiation of cells with elevated TORC1 activity under nutrient restriction. PLoS Genet. 14, e1007347 (2018).
Wong, K. K. L. et al. The nutrient sensor OGT regulates Hipk stability and tumorigenic-like activities in Drosophila. Proc. Natl Acad. Sci. USA 117, 2004–2013 (2020).
Hirabayashi, S. & Cagan, R. L. Salt-inducible kinases mediate nutrient-sensing to link dietary sugar and tumorigenesis in Drosophila. eLife 4, e08501 (2015).
Sanaki, Y., Nagata, R., Kizawa, D., Léopold, P. & Igaki, T. Hyperinsulinemia drives epithelial tumorigenesis by abrogating cell competition. Dev. Cell 53, 379–389.e5 (2020).
Willecke, M., Toggweiler, J. & Basler, K. Loss of PI3K blocks cell-cycle progression in a Drosophila tumor model. Oncogene 30, 4067–4074 (2011).
Wang, C.-W. W., Purkayastha, A., Jones, K. T., Thaker, S. K. & Banerjee, U. In vivo genetic dissection of tumor growth and the Warburg effect. eLife 5, e18126 (2016).
Wong, K. K. L., Liao, J. Z. & Verheyen, E. M. A positive feedback loop between Myc and aerobic glycolysis sustains tumor growth in a Drosophila tumor model. eLife 8, e46315 (2019).
Eichenlaub, T. et al. Warburg effect metabolism drives neoplasia in a Drosophila genetic model of epithelial cancer. Curr. Biol. 28, 3220–3228.e6 (2018).
Hirabayashi, S. The interplay between obesity and cancer: a fly view. DMM 9, 917–926 (2016).
Woodcock, K. J. et al. Macrophage-derived upd3 cytokine causes impaired glucose homeostasis and reduced lifespan in Drosophila fed a lipid-rich diet. Immunity 42, 133–144 (2015).
Zhou, J. & Boutros, M. JNK-dependent intestinal barrier failure disrupts host–microbe homeostasis during tumorigenesis. Proc. Natl Acad. Sci. USA 117, 9401–9412 (2020).
Ferguson, M. et al. Differential effects of commensal bacteria on progenitor cell adhesion, division symmetry and tumorigenesis in the Drosophila intestine. Development 148, dev186106 (2021).
Bangi, E., Pitsouli, C., Rahme, L. G., Cagan, R. & Apidianakis, Y. Immune response to bacteria induces dissemination of Ras-activated Drosophila hindgut cells. EMBO Rep. 13, 569–576 (2012).
Jacqueline, C. et al. The role of innate immunity in the protection conferred by a bacterial infection against cancer: study of an invertebrate model. Sci. Rep. 10, 10106 (2020).
Dvorak, H. F. Tumors: wounds that do not heal. N. Engl. J. Med. 315, 1650–1659 (1986).
Cohen, B. Nobel Committee rewards pioneers of development studies in fruit flies. Nature 377, 465 (1995).
Wieschaus, E. & Nüsslein-Volhard, C. The Heidelberg screen for pattern mutants of Drosophila: a personal account. Annu. Rev. Cell Dev. Biol. 32, 1–46 (2016).
Perrimon, N., Pitsouli, C. & Shilo, B. Z. Signaling mechanisms controlling cell fate and embryonic patterning. Cold Spring Harb. Perspect. Biol. 4, a005975 (2012).
Bangi, E. in Advances in Experimental Medicine and Biology Vol. 1167 (eds Crusio, W.E., et al.) 237–248 (Springer, 2019).
Sonoshita, M. & Cagan, R. L. Modeling human cancers in Drosophila. Curr. Top. Dev. Biol. 121, 287–309 (2017).
Rera, M., Vallot, C. & Lefrançois, C. The Smurf transition: new insights on ageing from end-of-life studies in animal models. Curr. Opin. Oncol. 30, 38–44 (2018).
Shirasu-hiza, M. M. & Schneider, D. S. Confronting physiology: how do infected flies die? Cell. Microbiol. 9, 2775–2783 (2007).
Mezdhitov, R., Schneider, D. & Soares, M. P. Disease tolerance as a defense strategy. Science 335, 936–941 (2012).
Rao, S. & Ayres, J. S. Resistance and tolerance defenses in cancer: lessons from infectious diseases. Semin. Immunol. 32, 54–61 (2017).
Dillman, A. R. & Schneider, D. S. Defining resistance and tolerance to cancer. Cell Rep. 13, 884–887 (2015).
Harshbarger, J. C. & Taylor, R. L. Neoplasms of insects. A. Rev. Ent. 12, 159–190 (1968).
Salomon, R. N. & Rob Jackson, F. Tumors of testis and midgut in aging flies. Fly 2, 265–268 (2008).
Siudeja, K. et al. Frequent somatic mutation in adult intestinal stem cells drives neoplasia and genetic mosaicism during aging. Cell Stem Cell 17, 663–674 (2015).
Hariharan, I. K. & Bilder, D. Regulation of imaginal disc growth by tumor-suppressor genes in Drosophila. Annu. Rev. Genet. 40, 335–361 (2006).
Stephens, R. et al. The scribble cell polarity module in the regulation of cell signaling in tissue development and tumorigenesis. J. Mol. Biol. 430, 3585–3612 (2018).
Rossi, F., Attolini, C. S. O., Mosquera, J. L. & Gonzalez, C. Drosophila larval brain neoplasms present tumour-type dependent genome instability. G3 8, 1205–1214 (2018).
Richardson, H. E. & Portela, M. Modelling cooperative tumorigenesis in Drosophila. Biomed. Res. Int. 2018, 4258387 (2018).
Bonello, T. T. & Peifer, M. Scribble: a master scaffold in polarity, adhesion, synaptogenesis, and proliferation. J. Cell Biol. 218, 742–756 (2019).
Bangi, E. et al. A personalized platform identifies trametinib plus zoledronate for a patient with KRAS-mutant metastatic colorectal cancer. Sci. Adv. 5, eaav6528 (2019).
Hou, S. X. & Singh, S. R. Stem-cell-based tumorigenesis in adult Drosophila. Curr. Top. Dev. Biol. 121, 311–337 (2017).
The authors thank D. Raulet and K. Evason for sharing expertise, and C. Liu, R. Boileau, A. Figueroa-Clarevega, A. Houser, S. Haraguchi and S. Zhou for important contributions to tumour–host work in the Bilder laboratory. This work has been supported by National Institutes of Health (NIH) grants GM130388, GM090150 and R21CA180107 to D.B., a University of California Cancer Research Coordinating Fellowship to T.-C.H. and a Mark Foundation Damon Runyon Fellowship (DRG 2400-20) to K.O. The authors acknowledge the superb and influential work of the late M. Vidal, a pioneer in the field.
The authors declare no competing interests.
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A signalling molecule produced by a tumour that is an effector of interactions with a host.
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Bilder, D., Ong, K., Hsi, TC. et al. Tumour–host interactions through the lens of Drosophila. Nat Rev Cancer 21, 687–700 (2021). https://doi.org/10.1038/s41568-021-00387-5