What makes cancer cells different from normal cells in our bodies? Can these differences be used to strike them and paralyze their activity? This fundamental question has troubled cancer researchers since the mid-19th century. The search for specific features of cancer cells is a building block of modern cancer research.
A new study led by researchers from Tel Aviv University shows, for the first time, how an abnormal number of chromosomes (aneuploidy) – a unique feature of cancer cells known to researchers has been known for decades – being a weak point for those. cells. The study could lead, in the future, to the development of drugs that use this vulnerability to destroy the cancer cells.
The study, published in Nature, performed in the laboratory of Dr. Uri Ben-David of the Faculty of Sackler Studies at Tel Aviv University, in collaboration with six laboratories from four other countries (the United States, Germany, the Netherlands, and Italy).
Aneuploidy is a sign of cancer. While normal human cells have two sets of 23 chromosomes each – one from the father and one from the mother – aneuploid cells contain a different number of chromosomes. When aneuploidy appears in cancer cells, not only do the cells “accept” it, but it can even promote the progression of the disease. The relationship between aneuploidy and cancer was discovered more than a century ago, long before cancer was known to be a genetic disease (and even before DNA was discovered as a hereditary material).
According to Dr. Ben-David, aneuploidy is the most common genetic variant in cancer. About 90% of solid tumors, such as breast cancer and colon cancer, and 75% of blood cancers, are aneuploid. However, our understanding of how aneuploidy contributes to the development and spread of cancer is limited.
In the study, the researchers used advanced bioinformatic methods to measure aneuploidy in approximately 1,000 cancer cell cultures. They then compared the genetic dependence and drug sensitivity of high aneuploidy cells with those of low aneuploidy cells. They found that aneuploid cancer cells exhibit a greater sensitivity to inhibition of the mitotic test site – a cell test site that ensures proper separation of chromosomes during cell division.
They also discovered the molecular basis for increased sensitivity of aneuploid cancer cells. Using genomic and microscopic techniques, the researchers discovered chromosome separation in cells treated with a substance known to inhibit the mitotic point of examination. They found that when the mitotic probe is moved into cells with the correct number of chromosomes, cell division stops. As a result, the chromosomes in the cells separate successfully, and very few chromosomal problems are formed. But when this mechanism is disrupted in aneuploid cells, cell division continues, resulting in the formation of many chromosomal changes that damage the ability of the cells to divide, and even cause the death.
The study has a significant impact on the drug detection process in the treatment of personalized cancer. Drugs that delay chromosome separation are going through clinical trials, but it is not known which patients respond and which do not. The results of this study suggest that it may be possible to use aneuploidy as a biological marker, based on the ability of patients to find a better response to these drugs. To put it another way, it will be possible to modify drugs that are already in clinical trials for use against tumors with specific genetic characteristics.
In addition, the researchers suggest focusing the development of new drugs on specific components of the chromosomal differentiation mechanism, which have been identified as particularly critical for aneuploid cancer cells. The mitotic lesion is composed of several proteins. The study shows that the sensitivity of aneuploid cells to inhibition of the different proteins is not the same, and that some proteins are more essential for cancer cells than others. Thus, the study provides an incentive to develop specific drugs against additional proteins in the mitotic study space.
It should be emphasized that the study of cells in culture and not on true tumors, and to translate them into the treatment of cancer patients, much more follow-up studies are needed. If true in patients, however, our findings would have several important medical implications. “
Dr. Uri Ben-David, Sackler Faculty of Science, Tel Aviv University
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Magazine Reference:
Cohen-Sharir, Y., et al. (2021) Aneuploidy removes cancer cells that are vulnerable to mitotic point inhibition. Nature. doi.org/10.1038/s41586-020-03114-6.