Chromosomal instability in colorectal cancer

Colorectal tumors are chromosomally unstable, which causes extensive cell-to-cell genome variation in the tumor. This was discovered by researchers from the group of Geert Kops at the Hubrecht Institute, in collaboration with researchers from the group of Hugo Snippert at the UMC Utrecht, and others, using patient-derived colorectal tumor organoids. This finding increases our understanding of the causes of genomic heterogeneity in cancer. They published their results in Nature Genetics on the 29th of April.

Mistakes in cell divisionHealthy 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 is the frequency by which cells make mistakes in chromosome segregation.

HeterogeneityAneuploidy is a hallmark of cancer, including colorectal cancer. However, it was unclear until now whether human tumors are chromosomally unstable as well, and therefore continue to make mistakes. Chromosomal instability increases the tumor karyotype heterogeneity: the karyotype, or chromosome content, differs between daughter cells after cell division. These differences affect treatment response of the tumor: some cells may respond to a certain treatment, while other, different, cells may not. This increases the risk of the cancer coming back after treatment. Therefore, learning more about chromosomal instability and its relationship with heterogeneity in tumors is of value for the development of cancer treatments in the future.

Healthy colon organoid | Gezond dikkedarm organoïde

Looking at cancer cellsAccording to the researchers, the best way to measure chromosomal instability is by looking at the process of chromosome segregation during cell division. “If you only look at chromosome numbers at a certain time point, which is what has been done until now, you miss valuable information that tells you whether the chromosome segregation mistakes are still ongoing in the tumor,” says Ana Bolhaqueiro, one of the researchers involved in the study. Because imaging cells in a living human tumor is not possible, they used organoids, mini-organs grown from a piece of tissue from a patient that resembles the original tissue very closely (Figure). By placing the organoids under a microscope, live segregation of chromosomes during cell division can be visualized, and the researchers can evaluate whether cell division happens correctly or incorrectly (Figure).

Tumors make mistakesThe researchers studied tumor organoids grown from the tumor of 11 patients with colorectal cancer. They found that the vast majority of colorectal tumors organoids makes many more mistakes than organoids from a healthy part of the colon. In addition, they observed that different regions in the same tumor can have different rates of mistakes in chromosome segregation. Moreover, when looking at the consequences of chromosome segregation errors by single-cell whole genome sequencing, they found that tumors with higher instability levels usually had more cell-to-cell genomic variability. The authors also found that not all tumors tolerated mistakes in mitosis equally well: some tumors were more resistant than others. Combining the extent of instability and the extent of tolerance to instability proved to be a good predictor of the extent of cell-to-cell genomic variability. These characteristics of tumor cells may influence their response to treatment.

If you only look at chromosome numbers at a certain time point, you miss valuable information that tells you whether the chromosome segregation mistakes are still ongoing in the tumor

Future implicationsPrevious studies have shown that when you increase chromosomal instability in already chromosomally unstable cells, this increases the chance that these cells will die. Organoids can be used in the future to study the synergy between chromosomal instability, tolerance for mitotic errors and drug response to improve cancer treatment in a patient and tumor specific way.

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.