image: (Left to right): Doctoral student Johanna Zerbib & Prof. Uri Ben-David
Credit: Tel Aviv University.
Two complementary studies from the Faculty of Medical and Health Sciences at Tel Aviv University, in collaboration with the European Institute of Oncology in Milan, have extensively examined the characteristics of cells with an abnormal number of chromosomes - known as aneuploid cells - and raised findings that may advance new cancer treatments. According to the researchers, "a significant portion of cancer cells are aneuploid, and this trait distinguishes them from healthy cells. Our work focuses on the vulnerabilities of aneuploid cells, with the aim of promoting new strategies for eliminating cancerous tumors. In our studies, we found that aneuploidy increases the sensitivity of cancer cells to certain types of anticancer drugs."
The studies were led by Prof. Uri Ben-David and doctoral student Johanna Zerbib from the Department of Human Molecular Genetics and Biochemistry at the Faculty of Medical and Health Sciences at Tel Aviv University, in collaboration with Professor Stefano Santaguida and doctoral student Marica Rosaria Ippolito from the University of Milan in Italy, along with researchers from both laboratories. Additional contributors included research teams in Israel, Italy, the USA, and Germany. Two articles based on the research were published in the prestigious journals Cancer Discovery and Nature Communications.
Prof. Ben-David explains: "In the nucleus of a healthy human cell, there are 23 pairs of chromosomes - half from the father and half from the mother, totaling 46. One of the characteristics of cancer cells, which distinguishes them from healthy cells, is an abnormal number of chromosomes, resulting from improper cell division - a phenomenon known as aneuploidy. We believe that if we can identify specific vulnerabilities of aneuploid cells, we can promote new cancer treatments that target these weaknesses and do not harm healthy cells. About three years ago, we published a comprehensive study in the journal Nature, in which we classified approximately 2,000 malignant cells from various cancer types according to their level of aneuploidy, and examined how they respond to a variety of existing treatments. In that study we found new vulnerabilities of aneuploid cells - however, the study had a limitation: because the cells came from different types of cancer, it was difficult to isolate the impact of aneuploidy itself from the effect of other genetic differences between the tumors."
Consequently, the researchers chose to conduct a new study using human cell cultures that are all genetically identical (i.e., derived from the same individual). The researchers added a substance to the cultures that disrupts the separation of chromosomes, causing some of them to become aneuploid. Since the cells were genetically identical, the only difference between them after the procedure was the level of aneuploidy - i.e., the number of chromosomes. To thoroughly examine the effects of aneuploidy, the cells underwent various characterization processes: DNA and RNA sequencing, measuring the levels of all the proteins in the cell, assessing the response to 6,000 different drugs, as well as a process known as CRISPR screening - systematically impairing each gene in the genome to identify genes that are essential in the cells. The researchers noted, "In this way, an extensive and unique database of the characteristics of aneuploid cells was established, which can serve as a foundation for future studies, as well as for developing biological markers that predict cancer patients' responses to specific drugs and treatments."
As part of the comprehensive survey, a mechanism called MAPK (mitogen-activated protein kinase) was observed, which is especially crucial for repairing DNA damage in aneuploid cells. The study also showed that this mechanism is relevant for various types of aneuploid cells—among them cancer cells in cultures and in human tumors. Prof. Ben-David: "We found that aneuploid cancer cells increase the activity of DNA repair mechanisms due to the large amount of DNA damage present; and we discovered a mechanism that could allow us to exploit this characteristic to target these cancer cells."
To test their hypothesis, the researchers disrupted the MAPK pathway in the cells and then examined their sensitivity to chemotherapy. The findings were promising: aneuploid cells in which this mechanism was disrupted were much more sensitive to chemotherapy (which causes DNA damage) compared to cells with a normal number of chromosomes. The researchers then sought to determine whether there is a correlation between this pathway and the clinical response of cancer patients to chemotherapy treatments. For this purpose, they relied on data from clinical treatments and experiments where human tumors were implanted in mice, and the results were clear: the higher the activity of the pathway in the aneuploid tumors, the greater their resistance to chemotherapy.
The comprehensive characterization of aneuploid cells also revealed another significant finding: these cells, which contain more chromosomes than normal cells, also necessarily contain a larger amount of DNA, leading to excess production of RNA and proteins. The cell, seeking to compensate for this overproduction, attempts to silence and degrade excess RNA and proteins. Johanna Zerbib noted: "We found here another vulnerability of aneuploid cells, based on our hypothesis that these cells are more sensitive to existing drugs that inhibit protein degradation. To validate this hypothesis, we exposed cell cultures to such drugs and analyzed clinical data from patients treated with a drug that inhibits protein degradation in the cells. The findings supported the hypothesis - aneuploidy increases the sensitivity of cancer cells to these drugs."
Prof. Ben-David concluded: "In our research, we identified two significant vulnerabilities characterizing aneuploid cells - cells with chromosomal changes that are commonly found in cancer cells. The first is a mechanism essential for repairing DNA damage, where impairment significantly increases the sensitivity of aneuploid cells to chemotherapy; the second is the increased degradation of excess RNA and proteins, which can be targeted, among other things, with inhibitors that are already in clinical use. We also created an extensive database of characteristics of aneuploid cells that can serve for predicting cancer patients' responses to various drugs and treatments. We believe that our research findings will benefit many researchers, oncologists, and patients in the years to come."
Please find below the links to the articles:
Cancer Discovery
https://aacrjournals.org/cancerdiscovery/article/doi/10.1158/2159-8290.CD-23-0309/747913
Nature Communications
https://www.nature.com/articles/s41467-024-52176-x
Journal
Cancer Discovery