Exploring the consequences of chromosomal instability in cancer

Chromosomal instability (CIN) is a process leading to chromosomal segregation errors. Aneuploidy, an abnormal number of chromosomes, is the consequence of chromosomal instability. CIN is a hallmark of human cancer that is associated with tumour heterogeneity, metastasis, and therapeutic resistance, which indicates that CIN is a promising target for cancer therapy. However, the role of CIN in tumour development and the molecular mechanisms that underlie CIN are still unclear. The main aim of this thesis is to investigate the multiple consequences of CIN and aneuploidy and to use this knowledge to explore strategies that can be exploited to selectively target tumours displaying CIN.Several mechanisms underlying CIN-induced stresses were discussed in this thesis. We also explored the possible strategies to target tumours displaying CIN, including exacerbating CIN to an unstainable level. To avoid the toxicity to normal cells, synthetic lethality with cancer-specific factors could prove to become a powerful strategy, including synthetic lethality with genes that are frequently overexpressed in cells that display CIN, identifying lethal interactions specifically in a CIN background, or (re)activating CIN-induced senescence. Altogether, our work provides several new leads that can be further explored for the future treatment of CIN tumours.

Dissertation: http://hdl.handle.net/11370/0701c725-dacf-4202-b318-0b4270e53a29