My group has been working on centrosomes for a long time and we are fascinated by these little organelles which are pretty much made up of proteins, they don’t contain anything else, yet they duplicate once per cell cycle which means that a cell either has got one centrosome or it has got two centrosomes, depending on where it is in the cell cycle. People have actually noticed over a hundred years ago that cancer cells often have more than two centrosomes which would suggest that they really have got a problem with maintaining normal centrosome numbers. They did propose that this could be important for the development of cancer. The people I’m talking about actually were Boveris, the couple who were working on chromosomes and centrosomes back in the early twentieth century. It was only recently found that in mice if mouse cells have got more than the normal centrosome content they actually do develop cancer more rapidly than normal mice.
What actually we did is we wanted to see whether centrosome abnormalities were very common in human tumours and for that we set up a collaboration with an ovarian cancer specialist from our institute whose name is James Brenton. With a PhD student, Gayathri Chandrasekaran, we methodically looked at centrosome numbers in many, many ovarian cancer samples. What we found is that actually over 60% of these samples have got massive centrosome amplification which means that their cells have got three, four, five, six centrosomes instead of the normal number. This is very interesting because we know that cells that have got extra centrosomes rely on particular molecular pathways to survive and this really opens up the possibility that we might be able to use this pathway or target this pathway to get rid of these highly abnormal cells.
Have any of these pathways been researched previously?
It depends on what area you work on. If you work on mitosis and you work on microtubule motors then this will be familiar because it is one of the microtubule minus end-directed motors called HSET. This is a kinase which is really important to so-called cluster the centrosomes. So cells that have got extra centrosomes, the way they survive is that they have to cluster these in so-called pseudo-bipolar spindles and this really makes sure that they can undergo bipolar divisions. A cell which has got too many centrosomes and it cannot cluster the centrosomes means that it’s going to go through multiple mitosis that’s going to lead to cell death.
Is the centrosomes amplification caused by a late stage cancer?
This is very hard to tell for ovarian cancer because most of the cancer patients we would see at the clinic, at Addenbrooke’s, they actually come with late presentation of the disease because ovarian cancer is usually noticed and diagnosed very late. This is why its survival rates are just so poor.
What follow-ups and further research will you be doing?
We already have followed this up to some extent. We actually have been working on HSET inhibitors; we have paired up with a chemistry group and another group from our institute, Duncan Jodrell’s group, and we did develop a new small molecule inhibitor of HSET. Obviously we have got issues and one of the main issues is that it has got cytotoxicity which we need to work on and we need to perfect this molecule and this is one of the things which we are planning to do over the next few years.