Understanding Replication Stress Can Help in Diagnosis and Treatment of Cancer

New study done by researchers
at University of Geneva (UNIGE) has shown that understanding of 'replication
stress' in cancer cells can help in better diagnosis and treatment of cancer.
When a cell divides into two
daughter cells, it must replicate its DNA according to a specific
scenario. In the presence of some
disruptive elements, however, cancer cells are unable to perform this operation
optimally; replication then takes place more slowly and less efficiently. This
phenomenon is called “replication stress”. While known to be linked to the
increase in genetic mutations, another phenomenon typical of cancer cells, the
exact mechanism at work remained unknown until now.
During a normal life cycle, the
cell grows and, when all the «building blocks» necessary for DNA replication
are ready, it replicates the chromosomes, which contain its genetic
information. Once DNA replication is complete, the cell enters in mitosis, a
term that refers to the steps governing cell division. A mitotic spindle is
then created, in which the two replicated DNA strands are separated so that the
two daughter cells inherit an identical number of chromosomes. “To ensure the
correct distribution of chromosomes, the mitotic spindle has two poles”, says
Patrick Meraldi, professor in the Department of Cell Physiology and Metabolism
and coordinator of the Translational Research Centre in Onco-haematology
(CRTOH) at UNIGE Faculty of Medicine. “This bipolarization is essential for the
genomic stability of both daughter cells.”
Most of the time, replication stress is due to certain molecules that, when
produced in excess, become harmful. For example, cyclin E protein, involved in
DNA regulation, promotes the development of cancers when overexpressed. Indeed,
under its influence, cancer cells tend to replicate too early. They do not have
all the components necessary for DNA synthesis yet, and this is where the
errors appear. How to create and remove replication stress To decipher this
phenomenon, the researchers artificially induced replication stress in healthy
human cells with a product that slows DNA replication, and thus prevents the
process from proceeding normally. “We have observed that this stress causes a
malformation of the mitotic spindle which, instead of having two poles, has
three or four”, explains Therese Wilhelm, a researcher in Professor Meraldi’s
team and co-first author of this work. “The cell is generally able to remove
these supernumerary poles, but not fast enough to avoid erroneous connections
between the chromosomes and the mitotic spindle.”
In the end, these erroneous connections promote a poor distribution of
chromosomes, leading to the loss or gain of one or more chromosomes. This
genetic instability thus allows the rapid anarchic evolution of cancer cells.
The scientists then successfully corrected the effects of replication stress in
diseased cells by providing them with the missing components they needed for
replication. “Not only have we established the link between replication stress
and chromosomal errors, but we have been able to correct it, showing that this
phenomenon, present in all cancer and even precancerous cells, is
controllable”, reports AnnaMaria Olziersky, a researcher in Professor Meraldi’s
team and co-first author. Could therapies exploit this phenomenon ? Through a
series of experiments targeting this mechanism, the researchers demonstrated
the greatest sensitivity of cells to the abnormal mitotic spindle to
paclitaxel, a chemotherapeutic drug acting on the mitotic spindle and used for
the treatment of breast cancer. “This shows that, in principle, it is possible
to specifically target these cells without affecting healthy cells”, explains
Patrick Meraldi. “The idea is not to correct the error, but rather to block the
cell at this stage to prevent it from removing the additional poles, which
automatically leads to its rapid death without causing damage to the still
healthy neighbouring cells.”
This research was funded by the Swiss National Science Foundation, the Swiss
Cancer League and the Ernest-Boninchi Foundation. CRTOH is part of the Swiss
Cancer Center Léman (SCCL), a multidisciplinary alliance bringing together the
UNIGE, HUG, EPFL, CHUV, UNIL and the ISREC Foundation to conduct fundamental,
translational and clinical research in the field of cancer.
The study report was published in Nature Communications journal.
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