Scheme: University Research Fellowship
Organisation: University of Cambridge
Dates: Oct 2010-Sep 2013
Summary: All living things are composed of cells that multiply through cell divisions. To match the needs of our body, in adult tissues cell divisions are kept in check by a powerful combination of internal and external quality control processes. Yet, once in a while, a control switch goes awry within a cell. If this faulty cell is not eliminated in time, it will inevitably proceed through a string of inaccurate cell divisions that cause further regulatory switches to fail. Such cells are the major culprits in the evolution of cancer, as their uncontrollable growth leads to tumours in vital organs. Tumours acquire an increasing number of irregularities as they expand, that include chromosome gains and losses, a sign that parental chromosomes are not shared equally between the daughter cells. Inheriting too many or too few chromosomes disrupts the normal physiology of daughter cells and contributes to the progression of cancer. Faithful segregation of the chromosomes relies on the microtubule cytoskeleton that essentially acts as cellular scaffolding. Microtubule behaviour on the other hand is regulated by a tiny organelle called the centrosome. Centrosomes contain hundreds of proteins and the role of these is largely obscure. Centrosome dysfunction is linked to several human diseases that include neurodevelopmental defects, polycystic kidney disease, obesity and cancer.
My laboratory studies the role of the centrosome in cell division and chromosome segregation. We want to shed lights on the multitude of control mechanisms that are responsible for microtubule organisation during cell division in healthy cells and reveal how their breakdown influences the development of cancer. Understanding the rules that govern microtubule organisation could also lead to therapeutical approaches. Indeed, compounds that disrupt microtubules have been in clinical use against breast and ovarian cancers for over a decade.
Dates: Oct 2005-Sep 2010
Summary: All living things are composed of cells that multiply through cell divisions. There are two types of cell division: meiosis is important for sexual reproduction and mitosis is responsible for growth, repair and cell replacement. The ultimate goal of mitosis is to produce two daughter cells with identical genetic content to the parental cell. A cell must therefore generate a perfect replica of its chromosomes and then partition the two sets equally into the daughters. What sorts of mechanisms allow the splitting of a cell into two is a fascinating question. Studying the principles that govern the formation of the mitotic spindle, the spindle-shaped structure responsible for the partitioning of chromosomes, is certainly a good place to start addressing this question. Mitotic spindles are formed by thousands of thin, thread-like structures, the microtubules. Spindle microtubules at one end are attached to chromosomes and at the other end are embedded in a small organelle, called the centrosome. The composition of the centrosome reflects its multiple roles. Being a major microtubule-organising centre, it is enriched in proteins that modulate microtubule behaviour, but it also houses many regulatory enzymes and structural proteins.
Much of our interest in the laboratory is focused on centrosome-resident proteins and their role in cell division.
By gaining insight into the molecular mechanisms that control microtubule organisation during cell division, we will be able to use our knowledge to develop new therapies. In particular, not only do cancer cells have aberrant microtubule organisation during cell division, but centrosome number and behaviour are also abnormal in tumours. Molecules known to disrupt microtubules have been in clinical use against breast and ovarian cancers for over a decade, indicating that microtubule behaviour is a valid therapeutical target.
Scheme: Dorothy Hodgkin Fellowship
Dates: Oct 2001-Sep 2005
Summary: This project summary is not available for publication.