Driving cancer cells to suicide
Every day, millions of cell divisions take place in our bodies. For a cell to give rise to two daughter cells, it must not only replicate its DNA, but also distribute the chromosomes evenly between the two new cells. This delicate distribution relies on a complex network of microtubules, coordinated by a pair of centrioles at each of its two poles.
In normal cells, the DNA and centriole cycles are coupled, but in many cancers these two cycles are out of synchronisation, causing deregulation of cell division. A few years ago, scientists in Prof. Patrick Meraldi's laboratory shed light on some of the mechanisms involved. They discovered that pairs of centrioles disconnect too early, creating three or four poles instead of the normal two. This anomaly leads to errors in chromosome distribution and encourages the uncontrolled, anarchic growth of cancer cells. However, the exact molecular mechanisms behind the desynchronisation between the two cycles remained to be elucidated.
Back to the origins of desynchronisation
Taking advantage of a microscope technique recently developed by Prof. Paul Guichard's laboratory at the Faculty of Science, Prof. Patrick Meraldi's research team from the Faculty of Medicine has been able to observe pairs of centrioles with previously unachieved spatial and temporal resolution. They discovered that the origin of the desynchronisation lies in the rate of activity of a protein called PLK1. PLK1 has long been known to play a key role in cell division, but the scientists have uncovered a difference in the sensitivity of the two cycles. In cancer cells, PLK1 is only 50% active, which is sufficient to advance the centriole cycle and separate centriole pairs, but delays the DNA cycle. In this way, cancer cells induce a moderate dose of stress that disrupts cell division without actually killing them.
On the left, in a normal cell, pairs of centrioles (in green) disconnect in time to create two poles and give rise to two daughter cells, whereas on the right, in a cancer cell, they disconnect too soon, creating too many poles. UNIGE - Laboratory of Prof. Patrick Meraldi
Rather than restoring the situation, exacerbating it and driving cancer cells to suicide
Given this differentiated response to a given PLK1 activity, the most promising strategy is surprisingly not to re-establish synchronisation between the two cycles, but to worsen the situation in order to block the cells in this situation, which will automatically force them to die. By slightly modifying PLK1 activity, we could induce a small increase in the level of stress. Healthy cells would be able to cope with this disturbance, whereas cancer cells that are already partly dysregulated would not be able to. A molecule capable of inducing cancer cells to commit suicide without affecting healthy cells would make it possible to limit the often severe side-effects of cancer treatments.