On 7 May, Dr Anabelle Decottignies, a bioengineer by training, an FNRS Senior Research Associate and the head of a research team at the de Duve Institute, received the Allard-Janssen Prize in support of her applied cancer research. What does her research contribute to the fight against cancer? And what hope does it generate?
For the past 15 years, Dr Decottignies has been working on the telomere, the structure located at the end of a chromosome that carries out a major mission: protecting the chromosome and allowing cell division. Telomeres play an important role in cell aging, but also in cancer. The telomere research group at the de Duve Institute, led by Dr Decottignies, recently set a goal to better understand the maintenance mechanism of telomeres in cancer cells in order to identify new targets in the fight against cancer.
Telomeres: biological clock
To understand their research, let’s start by understanding the function of telomeres in our healthy cells. Telomeres act as a biological clock governing the life of our cells. The more our cells divide, the more our telomeres wear out and shorten. The natural aging of cells can cause a decrease in immunity. However, as long as these divisions are limited, they have a protective effect, especially against the development of cancers. Thus, naturally, after some 50 divisions, our healthy cells can no longer divide.
Cancer cells have eternal youth
Most cancer cells, during their process of oncogenesis (when they acquire mutations that make them oncogenic), acquire mutations that make them immortal. Through this process, the cells are able to divide themselves to infinity. This eternal youth is called replicative immortality. In other words, cancer cells thwart the natural process of cell death. By foiling this process and multiplying to infinity, cancer cells accumulate and form metastases or tumours.
Telomerase: acquiring replicative immortality
To acquire this replicative immortality and multiply to infinity, cancer cells resort to two means. The first is to reactivate telomerase, a rejuvenating embryonic enzyme that helps maintain the size of telomeres. Indeed, at the embryo’s earliest development, a gene proving that embryonic cells are eternally young, is active. At this point, the cells can divide indefinitely thanks to a protein called telomerase. But soon after, the cells repress the expression of the gene responsible for this immortality, and the biological clock is triggered. In 90% of cancers, the telomerase encoding gene can wake up, causing infinite divisions and forming metastases and tumours.
An alternative mechanism called ALT
In 5 to 10% of cancers, a completely different mechanism is at work. This mechanism, called ALT (Alternative Lengthening of Telomeres), is poorly understood because it is inactive in our healthy cells. It was discovered in 1995 by the Australian group of Prof. Roger Reddel. With this ALT mechanism, the cell escapes the erosion of telomeres and divides indefinitely. How? No longer via the reactivation of telomerase, but via homologous recombination events between telomeric DNA sequences, which involve genetic and epigenetic malfunctions. This very particular mechanism of replicative immortality is active in certain tumours such as bone cancers (osteosarcomas), brain tumours (glioblastomas, especially paediatric ones) and neuroendocrine tumours.
Discovery of a specific target
The ALT mechanism is poorly known because it’s in healthy cells and barriers prevent it from occurring. Dr Decottignies’s team therefore wondered what the nature of these barriers was and performed genetic screenings with cells that follow this mechanism, comparing them with cells that reactivate telomerase. Thus the team found a potential target (a gene) that would kill the cell that uses the ALT mechanism, while completely sparing the healthy cells in our body. Its name? TSPYL5. With this target, anti-tumour treatment targeting ALT cancer cells and sparing healthy cells could be considered. So far, no one has found a molecular target specifically targeting the ALT mechanism that would spare healthy cells. Dr Decottignies and her team are thus making a giant leap in cancer research.
Through the subsidy awarded via the Allard-Janssen Prize, and in collaboration with chemists and structural biologists, Dr Decottignies’s team will be able to continue its work and try to find the molecule capable of specifically targeting the protein that is encoded by the TSPYL5 gene. The discovery of this molecule would allow for developing a targeted therapy in patients suffering from cancer for which this alternative mechanism is triggered. Dr Decottignies has hopes for this upcoming research. ‘One day I would like to treat cancers in children, without aging their precious healthy cells.’
A glance at Anabelle Decottignies's bio
1987-92 · Bachelor of Bioengineering, UCL
1992-98 · PhD thesis on drug resistance mechanisms (yeast as an example organism), Faculty of Agronomy, UCL
1999-2001 · Postdoctorate on cell cycle regulators (yeast as an example organism), Paul Nurse Cell Cycle Laboratory, London, Francis Crick Institute
2001-04 · FNRS Postdoctoral Researcher at UCL and de Duve Institute
2004 · FNRS Research Associate
2014 · FNRS Senior Research Fellow
2016 · Prix Fond Simon Bauvin, Christian Lispet, Robert Brancart, Denise Raes de la Fondation Roi Baudouin
December 2017 · Officier du Mérite wallon in the category ‘Sciences’
May 2018 · Allard-Janssens Prize