Genomic instability and cancer: lessons from Drosophila

Abstract

Cancer is a genetic disease that involves the gradual accumulation of mutations. Human tumours are genetically unstable. However, the current knowledge about the origins and implications of genomic instability in this disease is limited. Understanding the biology of cancer requires the use of animal models. Here, we review relevant studies addressing the implications of genomic instability in cancer by using the fruit fly, Drosophila melanogaster, as a model system. We discuss how this invertebrate has helped us to expand the current knowledge about the mechanisms involved in genomic instability and how this hallmark of cancer influences disease progression.

Keywords: DNA damage; Drosophila; aneuploidy; cancer; genomic instability.

Figure 1.

Responses to chromosomal instability. Errors of the mitotic machinery and its control mechanisms, such as the SAC, can trigger chromosomal instability. Diploid cells, including epithelial cells and stem cells, can undergo a mis-segregation of chromosomes, for example through multipolar mitosis. This can lead to aneuploidy, which describes the divergence from a diploid karyotype. In turn, the JNK stress signalling pathway is activated due to aneuploidy. This stress signalling mediates the removal of the damaged cells through apoptosis. For example, this is the case for wing imaginal epithelial cells. However, a resistance to apoptosis of cells can lead to tumorigenesis. This is the case for intestinal stem cells that generally do not undergo apoptosis. Epithelial cells that suppress apoptosis, for example through genetic manipulation, trigger tumorigenesis as well.

Figure 2.

Stress responses to aneuploidy and radiation. (a) Aneuploidy triggers both gene dosage imbalances and ER as well as proteotoxic stress. This leads together to oxidative stress and ROS accumulation. In turn, ROS can trigger JNK stress signalling. In parallel, cells activate p38 signalling, which can reduce the activity levels of the JNK pathway. In acentrosomal cells, the accumulation of ROS leads to induction of G6PD. This mechanism may also be present in aneuploid cells. It is likely that cells buffer JNK levels through p38 and potentially through G6PD to promote cytoprotective processes first, while higher levels of ROS and JNK activate apoptosis. (b) Radiation can trigger DNA damage. This activates primarily the DDR through the ATM/tefu–Chk2 and ATR/mei-41–Chk1 signalling branches. While both contribute to a genotoxic stress response through DNA repair, ATM/tefu–Chk2 mediates mostly p53-mediated apoptosis and can induce G2 cell cycle arrest after low-dose irradiation. ATR/mei-41–Chk1 signalling triggers G2 cell cycle arrest after strong irradiation. Additionally, the JNK stress signalling pathway is activated due to DNA damage. Both p53, which is activated through the DDR, and JNK mediate an apoptotic response in cells with high levels of DNA damage after irradiation. Similar to stress responses to aneuploidy, the involved pathways likely buffer apoptotic signalling to determine whether cells undergo cell cycle arrest and DNA repair or undergo cell death.

Figure 3.

Loss of chromosomal integrity and accumulation of mutations. (a) Ageing fly intestinal epithelia show frequent and spontaneous dysplastic growth arising from the intestinal stem cell population (green). These stem cells show frequent large-scale rearrangements in their chromosomes with increased age. In particular, the Notch locus, which is localized on the X chromosome, is frequently impaired and undergoes a loss heterozygosity leading to tumorigenic growth. Male flies in particular show frequent dysplasia due to the presence of one X chromosome. (b) The oncogene-induced DNA damage model describes how an initial oncogene activation can trigger broad DNA damage implications. In the first place, oncogenes, such as Ras or Cyclin E, can trigger DNA replication stress when the chromosomes are replicated during the cell cycle in S-phase. This can trigger DNA damages, and especially common fragile sites are susceptible to breaks and rearrangements. Additionally, tumorigenesis triggers copy number variations and single-nucleotide polymorphisms. Together, these processes can lead to an erosion of chromosomal integrity and broad changes to the encoded genetic information.

Figure 4.

Models to study the connection between genomic instability and tumorigenesis in flies. (a) The wing imaginal disc has been used extensively to model aspects of genomic instability in epithelial cells. In this tissue, spindle assembly errors trigger tumorigenesis in apoptosis-deficient cells through the JNK signalling axis. Similar to spindle assembly errors, ionizing radiation triggers neoplastic growth of epithelial cells that are apoptosis-deficient, and this tumorigenesis is enhanced by the depletion of DDR genes. Cytokinesis failure triggers the JNK pathway as well, and an introduction of the oncogene Yorkie leads to tumorigenesis that gives rise to highly polyploid cells. (b) Neuroblasts divide asymmetrically and the presence of centrosomes is essential for error-free mitosis in these cells. The ablation or mis-localization of centrosomes as well as supernumerary centrosomes can lead to tumorigenic neuroblasts. Transplantations of neuroblasts with centrosome defects form tumours in the abdomen of adult flies. (c) ISCs trigger dysplastic growth after spindle errors occur and behave similar to apoptosis-deficient epithelial cells. Similarly, ageing flies trigger frequently dysplasia originating from ISCs, and this is due to age-related somatic mutations.