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Tumour–host interactions through the lens of Drosophila

Abstract

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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Fig. 1: Drosophila organ systems and their human analogues.
Fig. 2: Interactions in the fly tumour microenvironment (TME).
Fig. 3: Paraneoplastic effects of fly tumours.

References

  1. 1.

    Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).

    CAS  PubMed  Google Scholar 

  2. 2.

    Pelosof, L. C. & Gerber, D. E. Paraneoplastic syndromes: an approach to diagnosis and treatment. Mayo Clin. Proc. 85, 838–854 (2010).

    PubMed  PubMed Central  Article  Google Scholar 

  3. 3.

    Fearon, K. C. H., Glass, D. J. & Guttridge, D. C. Cancer cachexia: mediators, signaling, and metabolic pathways. Cell Metab. 16, 153–166 (2012).

    CAS  PubMed  Article  Google Scholar 

  4. 4.

    Tisdale, M. J. Mechanisms of cancer cachexia. Physiol. Rev. 89, 381–410 (2009).

    CAS  PubMed  Article  Google Scholar 

  5. 5.

    Argilés, J. M., Stemmler, B., López-Soriano, F. J. & Busquets, S. Inter-tissue communication in cancer cachexia. Nat. Rev. Endocrinol. 15, 9–20 (2018).

    PubMed  Article  Google Scholar 

  6. 6.

    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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  7. 7.

    Cagan, R. L., Zon, L. I. & White, R. M. Modeling cancer with flies and fish. Dev.Cell 49, 317–324 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  8. 8.

    Bilder, D. & Irvine, K. D. Taking stock of the Drosophila research ecosystem. Genetics 206, 1227–1236 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  9. 9.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  10. 10.

    Hu, Y. et al. An integrative approach to ortholog prediction for disease-focused and other functional studies. BMC Bioinforma. 12, 357 (2011).

    Article  Google Scholar 

  11. 11.

    Bailey, M. H. et al. Comprehensive characterization of cancer driver genes and mutations. Cell 173, 371–385.e18 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  12. 12.

    Bilder, D. Epithelial polarity and growth control: links from the Drosophila neoplastic tumor suppressors. Genes Dev. 18, 1909–1925 (2004).

    CAS  PubMed  Article  Google Scholar 

  13. 13.

    Gonzalez, C. Drosophila melanogaster: a model and a tool to investigate malignancy and identify new therapeutics. Nat. Rev. Cancer 13, 172–183 (2013).

    CAS  PubMed  Article  Google Scholar 

  14. 14.

    Chatterjee, D. & Deng, W. M. Drosophila model in cancer: an introduction. Adv. Exp. Med. Biol. 1167, 1–14 (2019).

    CAS  PubMed  Article  Google Scholar 

  15. 15.

    Mirzoyan, Z. et al. Drosophila melanogaster: a model organism to study cancer. Front. Genet. 10, 51 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  16. 16.

    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.

    CAS  PubMed  Google Scholar 

  17. 17.

    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.

    CAS  PubMed  Article  Google Scholar 

  18. 18.

    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.

    CAS  PubMed  Article  Google Scholar 

  19. 19.

    Egeblad, M., Nakasone, E. S. & Werb, Z. Tumors as organs: complex tissues that interface with the entire organism. Dev. Cell 18, 884–901 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  20. 20.

    Maman, S. & Witz, I. P. A history of exploring cancer in context. Nat. Rev. Cancer 18, 359–376 (2018).

    CAS  PubMed  Article  Google Scholar 

  21. 21.

    Hanahan, D. & Coussens, L. M. Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell 21, 309–322 (2012).

    CAS  PubMed  Article  Google Scholar 

  22. 22.

    Binnewies, M. et al. Understanding the tumor immune microenvironment (TIME) for effective therapy. Nat. Med. 24, 541–550 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  23. 23.

    Patel, P. H., Dutta, D. & Edgar, B. A. Niche appropriation by Drosophila intestinal stem cell tumours. Nat. Cell Biol. 17, 1182–1192 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  24. 24.

    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.

    CAS  PubMed  Article  Google Scholar 

  25. 25.

    Vaccari, T. & Bilder, D. The Drosophila tumor suppressor vps25 prevents nonautonomous overproliferation by regulating notch trafficking. Dev. Cell 9, 687–698 (2005).

    CAS  PubMed  Article  Google Scholar 

  26. 26.

    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).

    CAS  PubMed  Article  Google Scholar 

  27. 27.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  28. 28.

    Martinez, A. M. et al. Polyhomeotic has a tumor suppressor activity mediated by repression of Notch signaling. Nat. Genet. 41, 1076–1082 (2009).

    CAS  PubMed  Article  Google Scholar 

  29. 29.

    Loubiere, V. et al. Coordinate redeployment of PRC1 proteins suppresses tumor formation during Drosophila development. Nat. Genet. 48, 1436–1442 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  30. 30.

    Baker, N. E. Emerging mechanisms of cell competition. Nat. Rev. Genet. 21, 683–697 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  31. 31.

    Madan, E., Gogna, R. & Moreno, E. Cell competition in development: information from flies and vertebrates. Curr. Opin. Cell Biol. 55, 150–157 (2018).

    CAS  PubMed  Article  Google Scholar 

  32. 32.

    Nagata, R. & Igaki, T. Cell competition: emerging mechanisms to eliminate neighbors. Dev. Growth Differ. 60, 522–530 (2018).

    CAS  PubMed  Article  Google Scholar 

  33. 33.

    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).

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  34. 34.

    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).

    CAS  PubMed  Article  Google Scholar 

  35. 35.

    Cordero, J. B. et al. Oncogenic ras diverts a host TNF tumor suppressor activity into tumor promoter. Dev. Cell 18, 999–1011 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  36. 36.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  37. 37.

    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).

    CAS  Article  Google Scholar 

  38. 38.

    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).

    CAS  PubMed  Article  Google Scholar 

  39. 39.

    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).

    CAS  PubMed  Article  Google Scholar 

  40. 40.

    Muzzopappa, M., Murcia, L. & Milan, M. Feedback amplification loop drives malignant growth in epithelial tissues. Proc. Natl Acad. Sci. USA 114, E7291–E7300 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  41. 41.

    Hayashi, S. & Kondo, T. Development and function of the Drosophila tracheal system. Genetics 209, 367–380 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  42. 42.

    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).

    CAS  Article  Google Scholar 

  43. 43.

    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.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  44. 44.

    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.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  45. 45.

    Mishra-Gorur, K. et al. Spz/Toll-6 signal guides organotropic metastasis in Drosophila. Dis. Model. Mech. 12, dmm039727 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  46. 46.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  47. 47.

    Calleja, M., Morata, G. & Casanova, J. Tumorigenic properties of Drosophila epithelial cells mutant for lethal giant larvae. Dev. Dyn. 245, 834–843 (2016).

    CAS  PubMed  Article  Google Scholar 

  48. 48.

    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).

    CAS  PubMed  Article  Google Scholar 

  49. 49.

    Potente, M., Gerhardt, H. & Carmeliet, P. Basic and therapeutic aspects of angiogenesis. Cell 146, 873–887 (2011).

    CAS  PubMed  Article  Google Scholar 

  50. 50.

    Noy, R. & Pollard, J. W. Tumor-associated macrophages: from mechanisms to therapy. Immunity 41, 49–61 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  51. 51.

    Lemaitre, B., Hoffmann, J. & Hoffman, J. The host defense of Drosophila melanogaster. Annu. Rev. Immunol. 25, 697–743 (2007).

    CAS  PubMed  Article  Google Scholar 

  52. 52.

    Banerjee, U., Girard, J. R., Goins, L. M. & Spratford, C. M. Drosophila as a genetic model for hematopoiesis. Genetics 211, 367–417 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  53. 53.

    Gold, K. S. & Brückner, K. Macrophages and cellular immunity in Drosophila melanogaster. Semin. Immunol. 27, 357–368 (2015).

    CAS  PubMed  Article  Google Scholar 

  54. 54.

    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).

    CAS  PubMed  Article  Google Scholar 

  55. 55.

    Theopold, U., Krautz, R. & Dushay, M. S. The Drosophila clotting system and its messages for mammals. Dev. Comp. Immunol. 42, 42–46 (2014).

    CAS  PubMed  Article  Google Scholar 

  56. 56.

    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.

    PubMed  PubMed Central  Article  Google Scholar 

  57. 57.

    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.

    CAS  PubMed  Article  Google Scholar 

  58. 58.

    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.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  59. 59.

    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).

    CAS  PubMed Central  Article  PubMed  Google Scholar 

  60. 60.

    Marcus, A. et al. in Advances in Immunology Vol. 122 91–128 (Academic, 2014).

  61. 61.

    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).

    PubMed  PubMed Central  Article  Google Scholar 

  62. 62.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  63. 63.

    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).

    PubMed  PubMed Central  Article  Google Scholar 

  64. 64.

    Kotsafti, A., Scarpa, M., Castagliuolo, I. & Scarpa, M. Reactive oxygen species and antitumor immunity — from surveillance to evasion. Cancers 12, 1–16 (2020).

    Article  CAS  Google Scholar 

  65. 65.

    Boccaccio, C. & Comoglio, P. M. Genetic link between cancer and thrombosis. J. Clin. Oncol. 27, 4827–4833 (2009).

    CAS  PubMed  Article  Google Scholar 

  66. 66.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  67. 67.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  68. 68.

    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).

    CAS  PubMed  Article  Google Scholar 

  69. 69.

    Gateff, E. & Schneiderman, H. A. Developmental capacities of benign and malignant neoplasms of Drosophila. W. Roux’ Archiv f. Entwicklungsmechanik 176, 23–65 (1974).

    CAS  Article  Google Scholar 

  70. 70.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  71. 71.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  72. 72.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  73. 73.

    Beaucher, M., Hersperger, E., Page-McCaw, A. & Shearn, A. Metastatic ability of Drosophila tumors depends on MMP activity. Dev. Biol. 303, 625–634 (2007).

    CAS  PubMed  Article  Google Scholar 

  74. 74.

    Stickel, S. & Su, T. T. Oncogenic mutations produce similar phenotypes in Drosophila tissues of diverse origins. Biol. Open 3, 201–208 (2014).

    PubMed  PubMed Central  Article  Google Scholar 

  75. 75.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  76. 76.

    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.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  77. 77.

    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).

    PubMed  PubMed Central  Article  Google Scholar 

  78. 78.

    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).

    Article  CAS  Google Scholar 

  79. 79.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  80. 80.

    Figueroa-Clarevega, A. & Bilder, D. Malignant Drosophila tumors interrupt insulin signaling to induce cachexia-like wasting. Dev. Cell 33, 47–55 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  81. 81.

    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.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  82. 82.

    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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  83. 83.

    Song, W. et al. Tumor-derived ligands trigger tumor growth and host wasting via differential MEK activation. Dev. Cell 48, 277–286 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  84. 84.

    Newton, H. et al. Systemic muscle wasting and coordinated tumour response drive tumourigenesis. Nat. Commun. 11, 4653 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  85. 85.

    Dev, R., Bruera, E. & Dalal, S. Insulin resistance and body composition in cancer patients. Ann. Oncol. 29, ii18–ii26 (2018).

    CAS  PubMed  Article  Google Scholar 

  86. 86.

    Wagner, E. F. & Petruzzelli, M. Cancer metabolism: a waste of insulin interference. Nature 521, 430–431 (2015).

    CAS  PubMed  Article  Google Scholar 

  87. 87.

    Huang, X. Y. et al. Pancreatic cancer cell-derived IGFBP-3 contributes to muscle wasting. J. Exp. Clin. Cancer Res. 35, 46 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  88. 88.

    Penna, F. et al. Muscle wasting and impaired myogenesis in tumor bearing mice are prevented by ERK inhibition. PLoS ONE 5, e13604 (2010).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  89. 89.

    Tisdale, M. J. Cancer anorexia and cachexia. Nutrition 17, 438–442 (2001).

    CAS  PubMed  Article  Google Scholar 

  90. 90.

    Patra, S. K. & Arora, S. Integrative role of neuropeptides and cytokines in cancer anorexia–cachexia syndrome. Clinica Chim. Acta 413, 1025–1034 (2012).

    CAS  Article  Google Scholar 

  91. 91.

    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.

    CAS  PubMed  Article  Google Scholar 

  92. 92.

    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).

    PubMed  Article  CAS  Google Scholar 

  93. 93.

    Colombani, J. et al. Drosophila Lgr3 couples organ growth with maturation and ensures developmental stability. Curr. Biol. 25, 2723–2729 (2015).

    CAS  PubMed  Article  Google Scholar 

  94. 94.

    Garelli, A. et al. Dilp8 requires the neuronal relaxin receptor Lgr3 to couple growth to developmental timing. Nat. Commun. 6, 8732 (2015).

    CAS  PubMed  Article  Google Scholar 

  95. 95.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  96. 96.

    Poillet-Perez, L. & White, E. Role of tumor and host autophagy in cancer metabolism. Genes. Dev. 33, 610–619 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  97. 97.

    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.

    CAS  PubMed Central  Article  PubMed  Google Scholar 

  98. 98.

    Rybstein, M. D., Pedro, B. S., JM, Kroemer, G. & Galluzzi, L. The autophagic network and cancer. Nat. Cell Biol. 20, 243–251 (2018).

    CAS  PubMed  Article  Google Scholar 

  99. 99.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  100. 100.

    Bridges, C. B. & Brehme, K. S. The Mutants of Drosophila melanogaster (Carnegie Institution, 1944).

  101. 101.

    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).

    Google Scholar 

  102. 102.

    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.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  103. 103.

    Caussinus, E. & Gonzalez, C. Induction of tumor growth by altered stem-cell asymmetric division in Drosophila melanogaster. Nat. Genet. 37, 1125–1129 (2005).

    CAS  PubMed  Article  Google Scholar 

  104. 104.

    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).

    CAS  PubMed  Article  Google Scholar 

  105. 105.

    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.

    CAS  PubMed  Article  Google Scholar 

  106. 106.

    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).

    PubMed Central  Article  PubMed  Google Scholar 

  107. 107.

    Romão, D., Muzzopappa, M., Barrio, L. & Milán, M. The Upd3 cytokine couples inflammation to maturation defects in Drosophila. Curr. Biol. 31, 1780–1787 (2021).

    PubMed  Article  CAS  Google Scholar 

  108. 108.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  109. 109.

    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).

    PubMed  PubMed Central  Article  Google Scholar 

  110. 110.

    Denholm, B. et al. The tiptop/teashirt genes regulate cell differentiation and renal physiology in Drosophila. Development 140, 1100–1110 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  111. 111.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  112. 112.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  113. 113.

    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).

    CAS  Article  Google Scholar 

  114. 114.

    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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  115. 115.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  116. 116.

    Hirabayashi, S. & Cagan, R. L. Salt-inducible kinases mediate nutrient-sensing to link dietary sugar and tumorigenesis in Drosophila. eLife 4, e08501 (2015).

    PubMed  PubMed Central  Article  Google Scholar 

  117. 117.

    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).

    CAS  PubMed  Article  Google Scholar 

  118. 118.

    Willecke, M., Toggweiler, J. & Basler, K. Loss of PI3K blocks cell-cycle progression in a Drosophila tumor model. Oncogene 30, 4067–4074 (2011).

    CAS  PubMed  Article  Google Scholar 

  119. 119.

    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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  120. 120.

    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).

    PubMed  PubMed Central  Article  Google Scholar 

  121. 121.

    Eichenlaub, T. et al. Warburg effect metabolism drives neoplasia in a Drosophila genetic model of epithelial cancer. Curr. Biol. 28, 3220–3228.e6 (2018).

    CAS  PubMed  Article  Google Scholar 

  122. 122.

    Hirabayashi, S. The interplay between obesity and cancer: a fly view. DMM 9, 917–926 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  123. 123.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  124. 124.

    Zhou, J. & Boutros, M. JNK-dependent intestinal barrier failure disrupts host–microbe homeostasis during tumorigenesis. Proc. Natl Acad. Sci. USA 117, 9401–9412 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  125. 125.

    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).

    CAS  PubMed  Article  Google Scholar 

  126. 126.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  127. 127.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  128. 128.

    Dvorak, H. F. Tumors: wounds that do not heal. N. Engl. J. Med. 315, 1650–1659 (1986).

    CAS  PubMed  Article  Google Scholar 

  129. 129.

    Cohen, B. Nobel Committee rewards pioneers of development studies in fruit flies. Nature 377, 465 (1995).

    CAS  PubMed  Article  Google Scholar 

  130. 130.

    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).

    CAS  PubMed  Article  Google Scholar 

  131. 131.

    Perrimon, N., Pitsouli, C. & Shilo, B. Z. Signaling mechanisms controlling cell fate and embryonic patterning. Cold Spring Harb. Perspect. Biol. 4, a005975 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  132. 132.

    Bangi, E. in Advances in Experimental Medicine and Biology Vol. 1167 (eds Crusio, W.E., et al.) 237–248 (Springer, 2019).

  133. 133.

    Sonoshita, M. & Cagan, R. L. Modeling human cancers in Drosophila. Curr. Top. Dev. Biol. 121, 287–309 (2017).

    CAS  PubMed  Article  Google Scholar 

  134. 134.

    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).

    PubMed  Article  Google Scholar 

  135. 135.

    Shirasu-hiza, M. M. & Schneider, D. S. Confronting physiology: how do infected flies die? Cell. Microbiol. 9, 2775–2783 (2007).

    CAS  PubMed  Article  Google Scholar 

  136. 136.

    Mezdhitov, R., Schneider, D. & Soares, M. P. Disease tolerance as a defense strategy. Science 335, 936–941 (2012).

    Article  CAS  Google Scholar 

  137. 137.

    Rao, S. & Ayres, J. S. Resistance and tolerance defenses in cancer: lessons from infectious diseases. Semin. Immunol. 32, 54–61 (2017).

    CAS  PubMed  Article  Google Scholar 

  138. 138.

    Dillman, A. R. & Schneider, D. S. Defining resistance and tolerance to cancer. Cell Rep. 13, 884–887 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  139. 139.

    Harshbarger, J. C. & Taylor, R. L. Neoplasms of insects. A. Rev. Ent. 12, 159–190 (1968).

    Article  Google Scholar 

  140. 140.

    Salomon, R. N. & Rob Jackson, F. Tumors of testis and midgut in aging flies. Fly 2, 265–268 (2008).

    PubMed  Article  Google Scholar 

  141. 141.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  142. 142.

    Hariharan, I. K. & Bilder, D. Regulation of imaginal disc growth by tumor-suppressor genes in Drosophila. Annu. Rev. Genet. 40, 335–361 (2006).

    CAS  PubMed  Article  Google Scholar 

  143. 143.

    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).

    CAS  PubMed  Article  Google Scholar 

  144. 144.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  145. 145.

    Richardson, H. E. & Portela, M. Modelling cooperative tumorigenesis in Drosophila. Biomed. Res. Int. 2018, 4258387 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  146. 146.

    Bonello, T. T. & Peifer, M. Scribble: a master scaffold in polarity, adhesion, synaptogenesis, and proliferation. J. Cell Biol. 218, 742–756 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  147. 147.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  148. 148.

    Hou, S. X. & Singh, S. R. Stem-cell-based tumorigenesis in adult Drosophila. Curr. Top. Dev. Biol. 121, 311–337 (2017).

    CAS  PubMed  Article  Google Scholar 

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Acknowledgements

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.

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Oncokine

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

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