The lab! L to R: Nadeem, Sarah McClelland ('Boss'), Alice, Laura, Naoka, Sarah Johnson, and Farheen (visiting student) (and in the window reflection is Enrique from another lab kindly acting as photographer...).

Our lab is interested in the mechanisms that maintain chromosome stability, and how those mechanisms are corrupted in cancer. To do this we work to understand mechanisms controlling normal chromosome replication and segregation. We also examine cancer cells in close detail to observe the precise kinds of mistakes they make while duplicating and segregating their chromosomes during each cell cycle.

NON-RANDOM CHROMOSOME MIS-SEGREGATION


We recently started to get fascinated by the fact that individual human chromosomes behave differently to one another during both mitosis and DNA replication (Worrall and Tamura et al, 2018; Tovini and McClelland, 2019, and unpublished work). Several ongoing projects in the lab are characterising this phenomenon in more detail, using imaging and single cell sequencing approaches.

Nadeem Shaikh - Post-Doc

Hello Alt
We are studying cancer at a molecular and genetic level. Ovarian cancer is the 5th most common cancer in women and often results in poor prognosis due to late diagnosis and limited treatment options. Pancreatic cancer survival rates have proven impossible to improve, remaining static at around 5%. We are investigating how chromosomal instability (CIN) might contribute to the difficulties in treating these diseases, with a view towards potentially reducing levels of CIN. This may retard the ability of these cancers to rapidly adapt to treatment. We are also studying how treating noncancerous cells with different types of mitotic or pre-mitotic stresses results in specific nonrandom patterns of aneuploidy.

Alice Mazzagatti - Post-Doc

Hello Alt
Aneuploidy - an abnormal number of chromosomes - is a common feature in human cancers and it is a consequence of chromosomal instability (CIN). Genomic instability is a hallmark of cancer cells that facilitates the acquisition of mutations conferring aggressive or drug-resistant phenotypes during cancer evolution.

We are studying the features of individual chromosome centromere biology underlying chromosome-specific aneuploidy, in order to define how these differences between human chromosomes can lead to increased chance that a particular chromosome will become aneuploid during tumourigenesis.

Laura Tovini - PHD Student

Determining the Contribution of Non-random Chromosome Mis-segregation to Clonal Evolution in Cancer

Every living cell of our body needs to keep under control the number and the structure of its chromosomes - the packages containing our genetic material. When this process fails, the cell can end up having an abnormal number of chromosomes. This feature - aneuploidy - is commonly observed in tumours and we still have to determine the underlying mechanisms of it, rendering the fight against cancer more difficult. It has earlier been assumed that all chromosomes behave in the same way inside the cell, and that they all have the same probability of being lost when something goes wrong. We are now trying to mimic the stressful conditions that can be present in cancer cells to understand if some chromosomes are more prone to be lost that others. Our method is carried out in laboratory using non-cancerous human cells and it involves the disruption of known proteins that move chromosomes during mitosis - the cell division process. In this way we can detect a potential difference in each chromosome’s behaviour in response to the stress induced. Later, we want to define patterns of aneuploidies for each chromosomes under different types of stress. We will further analyse these patterns in tumour samples, with the intention to better understand how cancer cells survive existing treatments and how we can better cure cancer patients in the future.

Sarah Clare Johnson - PHD Student

Hello Alt
Our cells organise their genetic material into packages called chromosomes. Whilst healthy cells strictly maintain the correct chromosome number, around 90% of cancer cells have completely abnormal numbers of chromosomes. These altered chromosome numbers are linked with more aggressive tumours which become resistant to chemotherapy more rapidly, and lead to poor patient survival. Despite this, it is not understood how abnormal chromosome number might be driving cancer, and why particular chromosomes are more frequently affected than others. As cancer cells have such chaotic chromosome profiles, rarely just affecting one chromosome at once, it is impossible to untangle the effect an individual chromosome change is having. Therefore, we have devised a new method to engineer cells with the single chromosomal losses/gains which are frequently seen in cancer, in a controlled manner in the laboratory. This will allow us to better understand how loss or gain of one individual chromosome affects a cell, and how this might be helping cancer to survive, grow and spread. Not only this, but this research could also reveal the vulnerabilities that specific chromosome changes expose cancer to. Understanding these weaknesses would allow us to assess which cancer therapy is best for a patient based on the chromosome profile of their tumour, and therefore offer better treatment.