Drug treatments lead to Correction of Aberrant Genome Behaviour in Cancer and Immortalised Cells
Gordon Memorial Fund
Principal investigator: Dr Joanna Bridger
Co-investigator: Dr Mai Hassan Ahmed
Co-investigator: Dr Mehmet Bikkul
Co-investigator: Ms Aakila Sammy
Our DNA/genome is segregated into 46 homologous chromosomes (apart from in the male – XY). Chromosomes and the genes contained upon them are non-randomly positioned in the nuclei of cells. The careful positioning of the genome within cells is regulated via nuclear structures such as the nuclear lamina, nucleoskeleton and nucleoli. These structures read reversible epigenetic signatures on the genes and chromosomes to associate and anchor them to specific regions of the nuclear landscape. This organisation appears to be to aid in the regulation of gene expression through spatial positioning, keeping the cell healthy and responding to external cues. However, this strict organisation of the genome can go array in cells that become unstable such as in cancer.
We have projects investigating aberrant genome organisation in female cancers - breast and ovarian. We have shown that chromosomes and genes are mis-positioned in a panel of breast cancer lines. Some of these cells have abnormal nuclear laminas and when this abnormal distribution of lamins was corrected with a new drug treatments the nuclear lamina anomalies were corrected as was the aberrant gene positioning. Furthermore, the drug treatment restored the normal levels of expression of genes associated with the cancer in one cell line (Hassan Ahmed et al., in prep. 2017; Wazir et al., 2013).
We have evidence from a study working with human telomerase reverse transcriptase (hTERT) immortalised cells that chromosome structure can also affect genome organisation. The addition of hTERT immortalises primary cells that no longer express it by allowing the telomeres to become elongated. Indeed, TERT is expressed in cancer cells which leads to immortalisation. In the cell lines we have investigated we have also found in addition that specific chromosomes are mis-localised in the cell nuclei. This abberant positioning can be corrected following drug treatments that permit the erosion of the elongated telomeres (Bikkul et al., in prep. 2017).