Aneuploidy, characterised by a deviation from the normal karyotype, is a common feature in cancer, being almost universal in solid tumours. The consequences of aneuploidy are usually deleterious for cells, involving dramatic changes in gene dosage that result in decreased robustness of biological networks. Consequently, aneuploidy is poorly tolerated by normal cells and its propagation is usually limited by mechanisms that maintain the genetic identity of these cells. However, chromosomal instability and the consequent karyotype heterogeneity are drivers of tumour evolution and cause the acquirement of therapy resistance. This paradox highlights the importance of understanding what makes cells tolerate or be intolerant of abnormal karyotypes. Our understanding of the pathways leading to the suppression of aneuploidy may be paramount to improving cancer treatment by allowing the uncovering of new therapeutic targets. To better understand how cancer cells tolerate aneuploidy, I used techniques of gene editing to modulate potential players in the suppression of chromosomal abnormalities caused by the disruption of spindle assembly checkpoint (SAC) function, then assessed the outcome by quantifying apoptotic events. I show here that both p53 and p38a are required for apoptosis in the presence of aneuploid cells; however, p38a has a more penetrant role in this mechanism. Further studies on the role of p38Î± in the suppression of aneuploidy showed that p38a-deficient cells upregulate the glycolytic metabolism and avoid postmitotic apoptosis, which correlates with the emergence of aneuploid subclones. Moreover, I show here that p38a-deficiency upregulates hypoxia-inducible factor 1 alpha (HIF-1a) and that, conversely, inhibiting HIF-1a restores apoptosis in p38a-deficient cells. The results presented in this thesis highlight a novel concept concerning two important natural barriers for tumour progressionânamely, aneuploidy and hypoxia. Given the ability of p38a-deficient cells to stabilise HIF-1a and the ability of HIF-1a to promote cell survival following chromosome missegregation, aneuploidy tolerance in mammalian cells may coevolve with an adaptation to hypoxia. Ultimately, this novel notion can have important implications for cancer therapeutics, potentially constituting the basis for the development of improved treatment strategies targeting a combination of mechanisms known for being drivers of tumour progression.
|Date of Award
|1 Aug 2019
- The University of Manchester
|Dean Jackson (Supervisor) & Stephen Taylor (Supervisor)