What sets cancer cells apart from normal cells in our body? And can this uniqueness be exploited to harm them and paralyze their operation? This basic question has been troubling cancer researchers since the mid-19th century to the present day, and the search for unique characteristics of cancer cells is a building block of modern cancer research. A new study led by researchers at Tel Aviv University shows for the first time how an abnormal number of chromosomes (anaploidy) – a unique feature of cancer cells that has been known to researchers for decades – can become a weak point of these cells. The study may lead in the future to the development of drugs that will exploit this vulnerability for targeted cancer cell damage.
The study, published in the prestigious journal Nature, was conducted in the laboratory of Dr. Uri Ben-David of the Sackler Faculty of Medicine, in collaboration with laboratories from five different countries: Dr. Zuzna Storkova (Kaiserslautern University of Technology, Germany), Dr. Jason Stampf (University of Vermont, USA), Dr. Stefano Santeguida (University of Milan, Italy), and Dr. Todd Golub (Broad Institute of MIT and Harvard, USA).
Following a 140-year-old mystery
Anaploidia is a hallmark of cancer. While in normal human cells there are two sets of 23 chromosomes, one from the father and one from the mother, in anaploid cells there are different numbers of chromosomes. When anaploidy is formed in cancer cells, not only can the cells “tolerate” it, but it can even promote the cancer process. The link between anaploidy and cancer was discovered nearly 140 years ago, long before the understanding that cancer was a genetic disease (and even before the discovery of DNA as a genetic material).
According to Dr. Ben-David, anaploidia is in fact the most common genetic change in cancer. About 90% of solid tumors, such as breast and colon cancer, and 75% of leukemias, are anaploid. However, we understand only to a limited extent. The way in which the phenomenon contributes to the development and spread of cancer.
In the study, the researchers applied advanced bioinformatics (computational) methods to detect anaploidy in about a thousand cancer cell cultures. The researchers then compared the genetic sensitivities of high-level anaploidy cells to those of low-level cells, as well as their susceptibility to various drugs and chemicals. The researchers found that anaploid cancer cells exhibit an increased susceptibility to damage to the chromosome separation mechanism during mitotic checkpoint.
In addition, the researchers discovered the molecular basis for the increased sensitivity of anaploid cancer cells. Using genomic and microscopic methods, the researchers monitored the separation of chromosomes in cells treated with a substance known as an inhibitor of the chromosome separation mechanism. The researchers found that when the mechanism is inhibited in cells with a normal chromosomal composition, cell division is stopped. As a result, the cells are able to perform proper separation of the chromosomes, and relatively few chromosomal problems arise. In contrast, when the mechanism is inhibited in anaploid cells, cell division continues, but is accompanied by the formation of many chromosomal changes, which impair the ability of cells to divide and even lead to their death.
Custom treatments
Research has important implications for the treatment process of customized cancer medicine. Drugs that inhibit the mechanism of chromosome separation are currently in clinical trials, but it is not known which patients will respond to the drugs and which will not. With the help of the study, it will be possible to use anaploidia as a biological marker on the basis of which it will be possible to locate the patients who will respond to these drugs better. That is, make an adjustment of existing chemotherapeutic drugs to tumors with specific genetic characteristics.
In addition, the researchers propose to focus the development of new drugs on specific components of the chromosome separation mechanism, which have been identified to be particularly critical for anaploid cancer cells. The control mechanism for chromosome separation consists of several proteins. The study shows that the susceptibility of anaploid cells to damage to the various proteins is not the same, and there are certain proteins whose damage is more severe. Thus, the study provides motivation to develop specific inhibitors of additional proteins in the control mechanism.
“It should be emphasized that the study was performed on cells in culture and not on cancer patients, and in order to translate it into the treatment of cancer patients, many more follow-up studies need to be done. -Uncle.