Page 10 - Keble Review 2014

10
The Keble Review 2014
Cell Divisio&n Cancer Dr Ulrike Gruneberg
Dr Gruneberg is a tutorial fellow in medicine with a focus on Cell Biology and Immunology. She is particularly interested in the cellular origins of cancer and the role of chromosome
tsegregation errors in tumorigenesis.
he mystery and beauty of cell division has fascinated daughter cells with equal numbers of chromosomes. It is extremely scientists for more than a century, ever since Walther important that this process is carried out correctly and that the Flemming described the events of nuclear division in physical cleavage of the mother cell into two only occurs when the
salamander cells in 1879. He discovered that cells contain a threadlike material that thickens into visible units during cell division. These units are then split apart longitudinally and are segregated to opposite poles of the cell. We now know that what Flemming observed were in fact the chromosomes containing the genetic material, but at the time this was not understood.
Since these early observations we have come a long way in understanding how cells segregate their genetic material and divide the cell body itself but many questions still remain open. For a start, it may be evident that cells have to divide to generate and maintain an organism, but it is not easy to comprehend how it is achieved that both daughter cells reliably obtain a complete set of chromosomes containing the full genetic material. Furthermore,
for a fertilized egg cell to develop into a fully grown organism a startling number of cell divisions have to occur. Even once that
has been accomplished, millions of cell division events continue to take place every second replenishing the supply of blood cells, skin cells and the lining of the gut. Yet diseases that are a consequence of errors in cell division, such as cancer, are relatively rare, and mostly occur in old age, suggesting that there are rigorous control mechanisms enforcing the correct segregation of the genetic material. Consequently, an accumulation of errors sufficient to give rise to cancerous progeny builds up only after many cell divisions. When errors in cell division occur they often result in the mis- segregation of chromosomes, resulting in cells containing either too few or too many chromosomes, a condition called aneuploidy. Aneuploidy gives rise to pools of cells with slight variations in their genomes and thus allows for selection of the fastest growing cancer cells, ultimately promoting tumour growth. Consequently, aneuploidy has long been considered a hallmark as well as a
driving force for cancer development. The significant incidence
of aneuploidy in cancer cells was noted by the German physician David von Hansemann in 1890 but the molecular insight into how aneuploidy arises is only now emerging. Work in my lab is aimed at understanding how the faithful division of the genetic material is accomplished and regulated, and how aneuploidy may be created when this process goes wrong.
When cells divide a number of events have to happen in a precisely ordered fashion; first the genetic material has to be duplicated
and then packed up into chromosomes. Next, for the purpose of segregating the chromosomes successfully into the two daughter cells, the chromosomes have to become attached to molecular strings called ‘microtubules’ and are then pulled apart by these to the two poles of the mother cell. Once the chromosome packages have been shared out, but not before, the cell is physically cleaved in half between the separated chromosome pools, thus forming two
chromosomes have successfully been divided up. Any disturbance of the temporal or spatial order of these events will lead to errors in cell division, resulting in the aforementioned aneuploidy or even cell death.
One important molecular cause for the development of aneuploidy is the presence of faulty connections between the chromosomes and the microtubule “strings”. Problems with the attachments between chromosomes and microtubules can result in chromosomes getting lost or ending up in the wrong cell when the chromosomes are shared out. My team is trying to understand in detail how the stable connections between microtubules and chromosomes are made and aneuploidy is avoided in healthy human cells, and which aspects of this process go wrong in disease situations such as cancer.
One particular goal of the lab is to unravel how an important cellular monitoring process, the “Spindle Assembly Checkpoint” functions. This molecular machinery checks that all chromosomes have successfully attached to the microtubule strings before the cell attempts to divide. This way the spindle assembly checkpoint safeguards the ability of the cell to share out the genetic material correctly. Some cancer cells appear to have a malfunctioning spindle assembly checkpoint, so detailed insight into how this important checkpoint process functions may provide vital clues for the further development of novel cancer therapies.
Another family of factors that affect the faithfulness of cell division are the protein regulators that control the working of the cell division machinery and make sure that the right events happen
at the right time. Recently my lab, in a joint effort with Professor Francis Barr’s lab at the Department of Biochemistry, identified
one such regulator of cell division, a protein called PP6. Research
by our labs demonstrated that PP6 prevents aneuploidy in normal cells by ensuring that the microtubule strings are arranged in an optimal way to capture the chromosomes. Analysis of tumour cells revealed that many skin cancers have defective versions of PP6 and that the loss of normal PP6 function is an early event on the path to cancer. Insights such as this, explaining what exactly goes wrong during cell division in cancer cells, is potentially of great value to human health, since drugs that interfere with cell division are widely and successfully used to treat cancer. However, many of the drugs commonly used in the clinic are either toxic to the patient
or cause the tumours to become resistant. New insights into the mechanisms of cell division may therefore reveal fresh avenues for therapeutic approaches in the fight against cancer.
Dr Ulrike Gruneberg
Fellow and Tutor in Experimental Pathology