5 March

Thesis defense Richard van Jaarsveld: From Harmony to Dissonance

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Richard van Jaarsveld from the Kops group successfully defended his thesis “From harmony to dissonance: An organoid-based study of chromosomal instability and aneuploidy in colorectal cancer progression” on the 5th of March. During his PhD, Van Jaarsveld studied the causes and consequences of chromosomal instability in colorectal cancer.

Aneuploidy and CIN
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 over the daughter cells. When errors occur in chromosome segregation this results in aneuploidy, an incorrect number of chromosomes in the cell, where one of the daughter cells will have too many chromosomes and the other will have too few. When cells repeatedly make mistakes in chromosome segregation this is called chromosomal instability (CIN). Many types of cancer, among which the majority of colorectal cancers, are both aneuploid and CIN. However, although around 80% of colorectal tumors are aneuploid, not all of them are also CIN. Aneuploidy can also result from an early mistake in chromosome segregation, while in later stages no additional segregation mistakes are made. Van Jaarsveld therefore concluded that studies on CIN should rely on the visualization of chromosome segregation during cell division, and not on the presence of aneuploidy.

Visualizing chromosome segregation in colon organoids
In agreement with his conclusion above, Van Jaarsveld studied CIN through visualization of chromosome segregation. He studied this chromosome segregation in mini-organs created from the colon, or colon organoids. Two main advantages of using such organoids are the presence of various colon cell types and more reliable chromosome segregation during cell division, associated with the 3D context of organoids. During his PhD, Van Jaarsveld analyzed hours upon hours of time-lapse movies of dividing cells in colon organoids, to score chromosome segregation errors. For such analyses he imaged growing colon organoids in which the DNA is fluorescently labeled over time, to be able to see the chromosomes segregate over the daughter cells (Figure 1).

Photo credit: Richard van Jaarsveld
Photo credit: Richard van Jaarsveld

Functions of p53 and p38 in CIN

Van Jaarsveld found in his studies that the loss of p53, a common tumor suppressor gene, induces CIN in colon organoids, which is a major hallmark of colorectal cancer. In addition, the loss of both the p53 and p38 proteins results in a specific type of mistake during chromosome segregation. He named these mistakes Bulky Anaphase Bridges (or BABs), based on the bridge between both daughter chromosomes that is visible under the microscope (Figure 2). The bridge contains proteins involved in DNA damage repair, suggesting that the loss of p53 and p38 allows a cell to start cell division while DNA damage is still being repaired. The proteins involved in DNA damage repair keep the daughter chromosomes together, which leads to the formation of a BAB and thereby prevents proper segregation. In the future, p38 inhibition may potentially be used to increase CIN in p53 deficient tumors, which will induce cell death and thereby kill the tumor cells.

 

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