21 June

Thesis defense Wilma Hoevenaar: Chromosomal instability in tumorigenesis

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Wilma Hoevenaar from the Kops group successfully defended her thesis “Chromosomal instability in tumorigenesis: The importance of how much, where and when” on the 20thof June. During her PhD, Hoevenaar developed a new model to study the role of chromosome segregation errors during cell division in the development and progression of cancer.

Mistakes in cell division
Healthy human cells contain 23 pairs of chromosomes, thus 46 chromosomes in total, that collectively form the human genome. During cell division these chromosomes need to be duplicated and segregated correctly to the daughter cells. When mistakes occur during the process of chromosome segregation this can result in aneuploidy, an incorrect chromosome content in the cell, where one of the daughter cells will have too many chromosomes and the other will have too few. Chromosomal instability, or CIN, is the frequency by which cells make mistakes in chromosome segregation.

A new model
Chromosomal instability is a process that should be followed over time, which makes it more difficult to study during tumor progression. During her PhD, Hoevenaar created a mouse model to study CIN in more detail during tumor progression. To this end, she targeted a gene called Mps1, a gene involved in making sure the segregation of chromosomes is done correctly. If the activity of this gene is lower, more mistakes are made during chromosome segregation. She made a mouse model with different variations of this gene: the normal fully function gene, a version with a lower activity, and a version with no activity at all. By combining these different variants of the gene in the same mouse, a range of total activity of the gene can be generated to study the effects of different levels of CIN in tumor progression. In addition, the researchers can choose the tissue and the moment in time at which the different versions of this gene are expressed. They called this mouse model CiMKi: Cre-inducible Mps1 Knock-in.

Examples of three different levels of chromomosome segregation errors, normal (no mistakes), mild and severe.

Unlimited possibilities
Using this model, Hoevenaar was able to show that the severity of mutations in the Mps1 gene is correlated with the number of chromosome segregation errors. In addition, the timing of the increase in chromosome segregation errors is important for the effect on tumor progression in mice intestinal cancer. The development of the CiMKi model opens doors to studying an almost unlimited number of questions regarding the role of CIN in cancer and to investigate possibilities for using CIN to target the tumor cells as well.

 

 

Geert Kops is group leader at the Hubrecht Institute, professor of Molecular Tumor Cell Biology at the University Medical Center Utrecht, Oncode Investigator and Scientific Director of Oncode Institute.