Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Cancer: The origin of genetic mutations

26.09.2019

By linking DNA replication failures in cancer cells to their genetic instability, researchers at UNIGE unveil a mutation mechanism that is essential for cancer development

When a cell divides into two daughter cells, it must replicate its DNA according to a very 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".


Fluorescence microscopy images of the division of a normal cell (left row) and a cell with replication stress (middle row). The mitotic spindle is in green, the chromosomes in red. The right row details the cell errors with replication stress: a three-pole spindle (left) and the loss of a chromosome (right).

Credit: © UNIGE -- Patrick Meraldi

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.

By deciphering how replication stress induces the loss or gain of whole chromosomes in the daughters of cancer cells, and even by reversing it in diseased cells, researchers at the University of Geneva (UNIGE) provide new knowledge that will ultimately lead to better diagnosis and possibly better treatment of cancer. Results can be discovered in the journal Nature Communications.

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 Anna-Maria 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.

Media Contact

Patrick Meraldi
Patrick.Meraldi@unige.ch
41-223-795-512

 @UNIGEnews

http://www.unige.ch 

Patrick Meraldi | EurekAlert!
Further information:
http://dx.doi.org/10.1038/s41467-019-11584-0

More articles from Life Sciences:

nachricht 'Flamenco dancing' molecule could lead to better-protecting sunscreen
18.10.2019 | University of Warwick

nachricht Synthetic cells make long-distance calls
17.10.2019 | Rice University

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Solving the mystery of quantum light in thin layers

A very special kind of light is emitted by tungsten diselenide layers. The reason for this has been unclear. Now an explanation has been found at TU Wien (Vienna)

It is an exotic phenomenon that nobody was able to explain for years: when energy is supplied to a thin layer of the material tungsten diselenide, it begins to...

Im Focus: An ultrafast glimpse of the photochemistry of the atmosphere

Researchers at Ludwig-Maximilians-Universitaet (LMU) in Munich have explored the initial consequences of the interaction of light with molecules on the surface of nanoscopic aerosols.

The nanocosmos is constantly in motion. All natural processes are ultimately determined by the interplay between radiation and matter. Light strikes particles...

Im Focus: Shaping nanoparticles for improved quantum information technology

Particles that are mere nanometers in size are at the forefront of scientific research today. They come in many different shapes: rods, spheres, cubes, vesicles, S-shaped worms and even donut-like rings. What makes them worthy of scientific study is that, being so tiny, they exhibit quantum mechanical properties not possible with larger objects.

Researchers at the Center for Nanoscale Materials (CNM), a U.S. Department of Energy (DOE) Office of Science User Facility located at DOE's Argonne National...

Im Focus: Novel Material for Shipbuilding

A new research project at the TH Mittelhessen focusses on the development of a novel light weight design concept for leisure boats and yachts. Professor Stephan Marzi from the THM Institute of Mechanics and Materials collaborates with Krake Catamarane, which is a shipyard located in Apolda, Thuringia.

The project is set up in an international cooperation with Professor Anders Biel from Karlstad University in Sweden and the Swedish company Lamera from...

Im Focus: Controlling superconducting regions within an exotic metal

Superconductivity has fascinated scientists for many years since it offers the potential to revolutionize current technologies. Materials only become superconductors - meaning that electrons can travel in them with no resistance - at very low temperatures. These days, this unique zero resistance superconductivity is commonly found in a number of technologies, such as magnetic resonance imaging (MRI).

Future technologies, however, will harness the total synchrony of electronic behavior in superconductors - a property called the phase. There is currently a...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

International Symposium on Functional Materials for Electrolysis, Fuel Cells and Metal-Air Batteries

02.10.2019 | Event News

NEXUS 2020: Relationships Between Architecture and Mathematics

02.10.2019 | Event News

Optical Technologies: International Symposium „Future Optics“ in Hannover

19.09.2019 | Event News

 
Latest News

Energy Flow in the Nano Range

18.10.2019 | Power and Electrical Engineering

MR-compatible Ultrasound System for the Therapeutic Application of Ultrasound

18.10.2019 | Medical Engineering

Double layer of graphene helps to control spin currents

18.10.2019 | Physics and Astronomy

VideoLinks
Science & Research
Overview of more VideoLinks >>>