A team of researchers led by scientists from Tel Aviv University says they may have encountered the ‘Achilles heel’ of cancer cells, which could lead to the development of an entirely new range of cancer drugs and treatments in the future.
Dr. Uri Ben-David of the Sackler Faculty of Medicine at Tel Aviv University, who led the study, says scientists have known for more than a century that malignant cells have an abnormal number of chromosomes.
An image from the Tel Aviv University-led study that found a weakness in cancer cells
(Image: Tel Aviv University)
Humans have 46 chromosomes (two sets of 23), but in cancer this number changes because during cell division chromosome segregation takes place that can lead to a phenomenon called aneuploidy.
Aneuploidy, the presence of an abnormal number of chromosomes in a cell, not only causes common genetic abnormalities, but is also a hallmark of cancer cells. Not all cancers show aneuploidy, but about 90% of solid tumors and 75% of blood cancers do to some degree.
According to Ben-David, the findings open a whole new path for medical research.
“We have been trying to understand why for decades [aneuploidy] happens in cancer and how it contributes to tumor formation and progression, ”says Ben-David.
Dr. Uri Ben-David
(Photo: Tel Aviv University)
More importantly, says Ben-David, scientists have been trying to see “if we can take advantage of this quite unique difference between cancer cells and normal cells to selectively kill the cancer cells.”
The study, which was published in the scientific journal Nature and whose findings were released Wednesday, was conducted in Ben-David’s lab at Tel Aviv University in collaboration with six laboratories in four other countries – the United States, Germany, The Netherlands and Italy.
“The general view here is that by understanding how aneuploid cells differ from normal cells, and by detecting the Achilles heel of aneuploid cells, this can be a very attractive way to selectively kill cancer cells,” says Ben-David.
Illustrative. A cancer patient undergoes an MRI scan
(Photo: Shutterstock)
In the study, researchers took about 1,000 cancer cell cultures from patients and viewed them in a lab using advanced bioinformatics methods to quantify their degree of aneuploidy, from the most aneuploidy to the least aneuploidy.
After the degree of chromosomal instability of the cancer cells was determined, the scientists examined and compared their sensitivity with thousands of drugs.
Scientists found that aneuploid cancer cells were highly sensitive to the disruption of the mitotic checkpoint – a so-called cellular mechanism that ensures proper separation of chromosomes during cell division.
“This allowed us to identify unique vulnerabilities of the aneuploid cells that we used and that we have extensively characterized at the molecular and cellular level,” says Ben-David.
“We found that if you inhibit the proteins of these pathways, the aneuploid cells are more sensitive to this interference than normal cells … therefore they are attractive targets for drug discovery and drug development.”
Illustrative. A cancer patient undergoing chemotherapy
(Photo: Shutterstock)
The research has important implications for future cancer treatments and personalized medicine. At present, several drugs that inhibit or slow chromosome separation are in clinical trials, but researchers have been unable to determine which patients would respond to them or not.
Ben-David’s study suggests that aneuploidy could help scientists determine an individual’s response to these drugs.
In addition, sharpening these chromosomal aberrations could also lead to the development of more effective cancer treatments in the future, as doctors can test for aneuploidy and design a treatment accordingly.
Dr. Yael Cohen-Sharir, from Tel Aviv University’s Department of Human Molecular Genetics and Biochemistry, is the lead author of the study. Cohen-Sharir, who manages Ben-David’s lab, called the research groundbreaking.
“Aneuploidy is very, very difficult to study,” she says. “It affects so many genes at once.”
Cohen-Sharir emphasizes that the current research has been conducted on cells in culture and not actual tumors, and that further follow-up research should be done. The next step for researchers, she says, is to try to replicate the findings on mice.
Cancer cells
(Illustration: Tel Aviv University)
As for Ben-David, he is optimistic that exploiting the unique features of aneuploidy could eventually lead to the holy grail of cancer research: finding a way to kill malignant cells without harming healthy cells in the body.
“Killing cancer cells is very simple: you can pour bleach on them and they will die, but the hardest part is doing it without killing normal cells,” he says.
Ben-David says this is, to his knowledge, the first time aneuploidy has been systematically evaluated in human cancer cells.
“That’s why it’s a big breakthrough,” he says.