Targeting aneuploidy, CIN and mechanisms of DNA content reduction in cancer
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Chromosomal instability (CIN) and aneuploidy are distinct events that can coexist in a tumour and one can result from the other. They can arise through direct errors in mitosis or in DNA damage repair and response machineries, DNA replication or chromatin remodelling that may allow damaged DNA to progress through cell cycle. Importantly, both CIN and aneuploidy can promote tumour initiation, progression and resistance to cancer therapies. Moreover, cell fusion is another mechanism that can lead to CIN or aneuploidy after chemotherapy or irradiation treatment. However, it can also cause tumour resistance and relapse, independently of aneuploidy and CIN, but currently, little is known about theses mechanisms. The overall aim of this PhD study was to identify novel targets in CIN and aneuploidy and to elucidate and target the mechanisms by which cell fusion can promote tumour relapse after chemotherapy treatment. Generation of different CIN and aneuploid models through errors in mitosis, DNA damage response/repair machineries or impaired chromatin remodelling, allowed the identification of hits dependent or independent of specific chromosome and gene alterations. Screening of CIN and aneuploid clones using a custom sgRNA library and confirmation by gene silencing and chemical inhibition, led to identification of synthetically lethal interactions between SETD7 depletion and BRG1 defects, TEX14-depletion and CENP-E-defects, HELQ-depletion and SWI/SNF-mutated models and PRIM1 depletion and CHK1-defective or SWI/SNF-mutated complex. In addition, we confirmed the induction of cell fusion due to Paclitaxel treatment and we identified and targeted, by screening of a small molecule library, the events by which tumour relapse occurs. Finally, we identified Crenolanib in sequential treatment with Paclitaxel as a new therapeutic approach in clinic to delay tumour recovery after Paclitaxel treatment. In summary, this PhD project proposes novel potential therapeutic targets and approaches in CIN and cell recovery after drug treatment, to improve cancer patient outcome.
Cancer - Genetics
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