Understanding chromosomal instability-induced senescence
[eng] Aneuploidy, defined as a chromosome number that deviates from a multiple of the haploid set, is a common feature in human cancer, and around 70% of human solid tumours are aneuploid. The resulting metabolic imbalance is proposed to play a fundamental role in the compromised fitness of these ce...
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| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2019 |
| País: | España |
| Institución: | Universidad de Barcelona |
| Repositorio: | Dipòsit Digital de la UB |
| OAI Identifier: | oai:diposit.ub.edu:2445/178622 |
| Acceso en línea: | https://hdl.handle.net/2445/178622 http://hdl.handle.net/10803/671915 |
| Access Level: | acceso abierto |
| Palabra clave: | Mort cel·lular Cromosomes Càncer Cell death Chromosomes Cancer |
| Sumario: | [eng] Aneuploidy, defined as a chromosome number that deviates from a multiple of the haploid set, is a common feature in human cancer, and around 70% of human solid tumours are aneuploid. The resulting metabolic imbalance is proposed to play a fundamental role in the compromised fitness of these cells and lead to malignant transformation by causing proteotoxic stress and affecting cell cycle proliferation and growth. However, most of the molecular pathways and cellular behaviours underlying aneuploid-induced tumorigenesis remain uncharacterized. Drosophila larval epidermal primordia have proved useful model systems to demonstrate the contribution of aneuploidy-induced metabolic stress to tumour growth. By depleting different Spindle Assembly Checkpoint (SAC) genes in the epithelial cells, we induce chromosomal instability and generate aneuploidy. When prevented from undergoing programmed cell death (PCD), these cells give rise to a neoplasic overgrowth. Here we propose that CIN-induced aneuploidy in epithelial cells activates low levels of the c-Jun N-terminal kinase (JNK) and the DNA damage response (DDR). This induces a G1 stall that prevents the accumulation of damage. However, when due to CIN these cells become highly aneuploid, they delaminate from the epithelium and acquire a senescent behaviour. This senescent behaviour is dependent on high levels of JNK and DDR signalling, and induce the secretion of wide variety of factors - also known as the senescence-associated secretory phenotype (SASP) -, and a permanent G2 arrest, among other senescent features. In addition, we have identified two target effectors, Fizzy-related and String, that are miss-regulated and could act downstream JNK and the DDR to induce the G2 arrest. Finally, we were able to explore two different ways to target CIN-aneuploid cells based on their basal levels of replicative stress: genetic (CycE/Dap overexpression) and chemical (Hydroxyurea), which significantly affect tissue growth and impair tumour progression. |
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