Abstract:Aneuploidy is associated with different human diseases including cancer. However, different cell types appear to respond differently to aneuploidy, either by promoting tumorigenesis or causing cell death. We set out to study the behavior of adult Drosophila melanogaster intestinal stem cells (ISCs) after induction of chromosome missegregation either by abrogation of the spindle assembly checkpoint or through kinetochore disruption or centrosome amplification. These conditions induce moderate levels of aneuploi… Show more
“…However, in contrast to imaginal cells, ISCs do not undergo apoptosis and, instead, overproliferate causing the formation of tissue dysplasia [23,25]. ISCs are resistant to apoptotic signalling, and this may be central explaining the pro-tumorignic role of JNK in this specific cellular context [25,38]. In agreement with this, cultured mammalian embryonic stem cells tolerate aneuploidy and polyploidy without undergoing apoptosis [39].…”
Section: Chromosome Instability In Stem Cellsmentioning
confidence: 85%
“…This approach also reveals that fly neoplasms show GIN and accumulate SNPs as well as CNVs that are in the range of human cancers [ 172 ]. Additionally, ISCs have been helpful in the study of stem cells and an analysis of ageing in adult flies [ 25 , 138 ] ( figure 4 c ). Figure 4.…”
Section: Discussionmentioning
confidence: 99%
“…As observed in the imaginal epithelium, aneuploid ISCs activate the JNK pathway. However, in contrast to imaginal cells, ISCs do not undergo apoptosis and, instead, overproliferate causing the formation of tissue dysplasia [23,25]. ISCs are resistant to apoptotic signalling, and this may be central explaining the pro-tumorignic role of JNK in this specific cellular context [25,38].…”
Section: Chromosome Instability In Stem Cellsmentioning
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.
“…However, in contrast to imaginal cells, ISCs do not undergo apoptosis and, instead, overproliferate causing the formation of tissue dysplasia [23,25]. ISCs are resistant to apoptotic signalling, and this may be central explaining the pro-tumorignic role of JNK in this specific cellular context [25,38]. In agreement with this, cultured mammalian embryonic stem cells tolerate aneuploidy and polyploidy without undergoing apoptosis [39].…”
Section: Chromosome Instability In Stem Cellsmentioning
confidence: 85%
“…This approach also reveals that fly neoplasms show GIN and accumulate SNPs as well as CNVs that are in the range of human cancers [ 172 ]. Additionally, ISCs have been helpful in the study of stem cells and an analysis of ageing in adult flies [ 25 , 138 ] ( figure 4 c ). Figure 4.…”
Section: Discussionmentioning
confidence: 99%
“…As observed in the imaginal epithelium, aneuploid ISCs activate the JNK pathway. However, in contrast to imaginal cells, ISCs do not undergo apoptosis and, instead, overproliferate causing the formation of tissue dysplasia [23,25]. ISCs are resistant to apoptotic signalling, and this may be central explaining the pro-tumorignic role of JNK in this specific cellular context [25,38].…”
Section: Chromosome Instability In Stem Cellsmentioning
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.
“…Quite fittingly, it was recently reported that aneuploidy in Drosophila Intestine Stem Cells (ISCs) results in increased stem-cell proliferation. Interestingly, ISCs do not activate apoptotic pathways in response to aneuploidy, suggesting that this type of cell is somewhat resistant to genomic imbalance [62]. Unusual resistance to altered ploidy was also observed in human and mouse embryonic stem cells (ESCs), mostly achieved by relaxing the cell-cycle control and uncoupling the spindle checkpoint from apoptosis [63].…”
Studying aneuploidy during organism development has strong limitations because chronic mitotic perturbations used to generate aneuploidy usually result in lethality. We developed a genetic tool to induce aneuploidy in an acute and time-controlled manner during
Drosophila
development. This is achieved by reversible depletion of cohesin, a key molecule controlling mitotic fidelity. Larvae challenged with aneuploidy hatch into adults with severe motor defects shortening their life span. Neural stem cells, despite being aneuploid, display a delayed stress response and continue proliferating, resulting in the rapid appearance of chromosomal instability, a complex array of karyotypes, and cellular abnormalities. Notably, when other brain-cell lineages are forced to self-renew, aneuploidy-associated stress response is significantly delayed. Protecting only the developing brain from induced aneuploidy is sufficient to rescue motor defects and adult life span, suggesting that neural tissue is the most ill-equipped to deal with developmental aneuploidy.
“…Drosophila midgut ISC mitosis is controlled by key signaling pathway ligands, including Delta, upd1-3, vein, dilp3,6 and eiger (Doupe, 2018), but mitosis can be diverted towards dysplasia due to deregulation of many of the same signaling pathways these ligands may control (Apidianakis 2009;Biteau 2008). Adult midgut dysplasia in Drosophila has been characterized by the widespread, irreversible and progressive loss of proper cell differentiation due to accumulation of groups of ISC-like and EE cells (Apidianakis, 2009;Biteau, 2008;Resende, 2018), and it is to be contrasted with the rare ISC-like/EE large tumors caused by spontaneous loss of heterozygosity of notch in old flies (Siudeja, 2015). A common property of differentiating Drosophila cells that need to cope with tissue development and homeostasis is endoreplicative cell growth.…”
Inflammatory signaling supports host defense against infection, not only through immune cells, but also via regeneration of damaged tissue. Heightened regeneration, nevertheless, predisposes for all types of cancer and thus a trade-off exists between regeneration capacity and long-term tissue homeostasis. Here, we study the role of tissue-intrinsic regenerative inflammatory signaling in stem cell mitosis of the adult Drosophila midgut at the baseline and the infected state and its impact on intestinal host defense to infection and stem cell-mediated dysplasia. Through a quantitative genetics screen we find that stem cell mitosis is positively linked with the expression of eiger, Delta, upd3 and vein in the midgut, as well as with dysplasia and host defense, but negatively with enterocyte endoreplication. We provide evidence that intertwined trade-offs fine-tune midgut homeostasis, according to which stem cell mitosis through cyclin E in stem cells promotes the optimal host defense to infection, unless dysplasia ensues. However, cyclin E in enteroblasts promotes enterocyte endoreplication and counterbalances stem cell mitosis and dysplasia, providing an alternative but less efficient mechanism to support host defense.
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