Risk and opportunity at the same time: the surplus chromosomes of many cancer cells make tumors more aggressive, but can also be used to fight cancer, as a study has now revealed. On the one hand, the chromosome copies multiply many cancer genes that stimulate tumor growth. At the same time, however, they provide starting points for new cancer therapies. Because the additional chromosomes also carry genes that make the cancer cells more susceptible to certain drugs, according to the researchers in “Science”.
If cells degenerate, this can usually be read from their chromosomes. Because of faulty cell divisions, cancer cells often get more than the normal number of chromosomes. The tumor cells affected by this aneuploidy then carry one or more copies of chromosomes. Some giant cancer cells can even have eight to 16 times the number of chromosomes. But whether this surplus of genetic material is merely a consequence of cell degeneration or perhaps even a cause of cancer has been a matter of debate up until now.
“High levels of aneuploidy in a cancer tumor are usually associated with poorer prognosis for the affected patients,” explain Yale University’s Vishruth Girish and his colleagues. “But whether this altered number of chromosome copies actively drives tumor growth, or whether aneuploidy is simply a risk factor in general, was less clear.”
Extra chromosomes make cancerous tumors more aggressive
To answer this question, the team first examined more than 23,500 cancer patients to see whether supernumerary copies of certain chromosomes or parts of chromosomes are associated with aggressive cancer growth and an unfavorable outcome more frequently than others. This was confirmed: If some DNA sections are present in more copies than normal, including the so-called q arm of the first chromosome, this promotes tumor growth in many types of cancer.
This was confirmed in tests with cell cultures of various types of cancer: Using a method based on CRISPR gene scissors, the researchers removed the third, excess copy of the 1q-CH chromosome arm from these cells and observed the resulting tumor growth. The result: The cells with the normalized number of copies produced smaller tumors, sometimes even no tumors at all.
Aneuploidy as a driver of degeneration?
“We also discovered that the extra copies of the 1q arm is often the first chromosome number abnormality that breast cancer cells develop,” report Girish and his team. “We therefore suspected that this aneuploidy of the first chromosome is not only necessary for cancer growth, but maybe even actively promotes the degeneration of cells.” This was also confirmed in an experiment with genetically “trimmed” cells.
Also interesting: cancerous tumors apparently take care of maintaining and regaining their 1q aneuploidy as far as possible. When the scientists allowed cultures of cancer cells that had been stripped of their third copy of the chromosome to grow, the number of cells with 1q aneuploidy increased again over time until they again constituted the majority.
Increased activity of cancer genes
But why are the chromosome copies so important for the cancer cells? Analyzes of gene expression provided an answer: several cancer-promoting genes, including MDM4, are located on the chromosome arm, which is present in triplicate in the cancer cells, as Girish and his team discovered. Because these oncogenes are present in multiples due to the aneuploidy, they are also transcribed to a greater extent and thus promote the degeneration of the cell.
At the same time, the increased activity of the oncogenes also suppresses the effect of the cell’s own countermeasures, for example through the protein p53, which acts as a tumor suppressor. The researchers suspect that this mechanism also comes into play in other cancer-typical aneuploidies and the genes located on the copied chromosomes – and thus promotes degeneration and tumor growth.
Copied genes as Achilles heel
The exciting thing, however, is that the dependence of cancer cells on their additional chromosome copies also opens up new starting points for cancer therapy. Because with the DNA copies, genes are also copied and become overactive, which can make the cancer cells more susceptible to certain active substances, as the researchers explain. If, for example, more membrane pumps or enzymes are produced as a result, this can increase the effect of chemotherapeutic agents.
This was confirmed in the 1q aneuploid cells. They show an overproduction of the enzyme UCK2, as Girish and his team discovered. In their experiments, these tumor cells were more sensitive to two experimental chemotherapeutic agents: in normal cancer cell cultures, which initially contained 20 percent aneuploid cells, these multiplied rapidly and accounted for 75 percent of the cell culture after nine days. However, when the researchers added the two experimental inhibitors, the proportion of aneuploid cancer cells in the culture dropped to just four percent.
Starting point for new cancer therapies
“This shows us that aneuploidy can offer a potential target for cancer therapies,” says senior author Jason Sheltzer from Yale University. “If we can selectively attack cells with excess chromosomes, then we could fight cancer without doing more damage to normal, non-degenerative tissue.”
However, it will be a while before these findings become applicable cancer therapies. The research team now plans to test other active substances on aneuploid cancer cells and to carry out animal experiments next. Only when these prove to be successful and safe would the first clinical studies with humans be possible. (Science, 2023; doi:10.1126/science.adg4521 )