Dividing cells are the engine of life.
One cell divides to become two. Two become four. Four become eight, then more.
But this process, which generates all living things – from the smallest bacterium to the biggest blue whale – is also at the heart of cancer, as out of control cells divide to form tumours.
Over the years we’ve funded world-leading research revealing the molecular nuts and bolts that cells use to divide, paving the way for potential new cancer treatments.
This has led to the discovery of how the timing of cell division is controlled, so that cells usually only multiply when they’re needed. And researchers now know how DNA is copied and the resulting two sets of genetic information get dished out between the two new ‘daughter’ cells, meaning that each one has the correct amount.
They also understand the complex system of checkpoints that cells use to make sure that nothing has gone wrong along the way. And, of course, they now know a lot about how all these processes can go wrong in cancer.
Now scientists at our Manchester Institute have made another discovery, with important implications for certain drugs that are undergoing clinical trials.
The new study, led by Drs Angeliki Malliri, Helen Whalley and Andrew Porter – published in the journal Nature Communications – focuses on tiny structures called centrosomes. These are the large white dots in the middle of the image of the cell above, seen down a high-powered fluorescence microscope.
Centrosomes are the cell’s scaffolding engineers, responsible for building long, tube-like structures called microtubules. They play a fundamental role as cells divide, generating a moving molecular scaffold that pulls apart the DNA.
Each cell usually has just one centrosome, but when it’s time for a cell to divide the single centrosome gets duplicated, along with the cell’s DNA. Next, one centrosome moves to each end of the cell (the red dots in the image on the right) and together they start constructing a network of microtubules (green lines), reaching towards the DNA (blue blobs) in the centre.
The microtubules grab hold of the DNA and pull the two copies apart. Then the cell splits down the middle, producing two identical ‘daughters’, each with one full set of DNA and one centrosome. And so the cycle repeats.
The Kinesin connection
Angeliki and her team have been studying a molecule called Kinesin-5 (also known as Eg-5), which is essential for centrosomes to function properly. Without it, the centrosomes don’t separate after they’ve been copied, remaining in the centre of the cell rather than moving to each end.
This leads to some pretty weird attempts at cell division. For example, in the image on the right – microtubules (green) radiate out from centrosomes (red) in the centre of the cell and capture DNA (blue) in a circle around them.
This molecular chaos is too much for cells to cope with – they get stuck, and eventually die. Because of this, researchers have wondered whether interrupting this process could help target cancer cells.
In their new paper, the Manchester team have discovered that reducing the levels of two other molecules, Pak1 and Pak2, enables cells to somehow carry on and divide, even in the presence of Monastrol.
Their finding has important implications for the development of Kinesin-5 blockers, because it suggests a way that cancer cells could develop resistance to them. Tumour cells are constantly evolving, so if they develop any genetic faults that block Pak1 or Pak2 then they might be able to keep growing, regardless of the treatment.
This could be used to help predict which patients will benefit most from these treatments. And understanding how cancers develop resistance to drugs – in this case while the treatments are still in early trials – will help the development of new strategies to overcome resistance and treat the disease more effectively.
At the moment, this research has been done using cells growing in the lab, so more work needs to be done to figure out whether this is something that happens in real tumours in patients. But this kind of detailed fundamental research is vital if we’re to truly understand cancer and beat it.
- Whalley, H., et al. (2015). Cdk1 phosphorylates the Rac activator Tiam1 to activate centrosomal Pak and promote mitotic spindle formation Nature Communications, 6 DOI: 10.1038/ncomms8437