Israeli scientists say they found ‘Achilles heel’ of cancer cells

Dr Uri Ben-David of Tel Aviv University’s Sackler Faculty of Medicine, who led the research, says scientists have known for more than a century that malignant cells have abnormal numbers of chromosomes.

Humans have 46 chromosomes (two sets of 23) but in cancer this number changes because during cell division chromosomal segregation occurs which can lead to a phenomenon called aneuploidy.

Aneuploidy, the presence of an abnormal number of chromosomes in a cell, not only causes common genetic disorders, but is also a hallmark of cancer cells. Not all cancers have aneuploidy, but about 90% of solid tumors and 75% of blood cancers do, to some extent.

According to Ben-David, the findings open up an entirely new avenue for medical research.

“For decades we have been trying to understand why [aneuploidy] occurs in cancer and how it contributes to the formation and progression of the tumor, ”says Ben-David.

More importantly, says Ben-David, scientists have been trying to see “if we can take advantage of this very unique difference between cancer cells and normal cells in order to selectively kill cancer cells.”

The study, which was published in the scientific journal Nature and the results of which were published on Wednesday, was conducted in Ben-David’s lab at Tel Aviv University in collaboration with six labs in four other countries – the United States, Germany, the Netherlands and Italy.

“The big picture here is that by understanding how aneuploid cells are different from normal cells and by detecting the Achilles heel of aneuploid cells, it could be a very attractive way to selectively kill cancer cells,” Ben says. David.

In the study, researchers took approximately 1,000 cultures of cancer cells from patients and examined them in a laboratory using advanced bioinformatics methods to quantify their degree of aneuploidy, from most aneuploidy to lesser aneuploidy.

Once the degree of chromosomal instability of cancer cells was determined, scientists then examined and compared their sensitivity to thousands of drugs.

Scientists have found that aneuploid cancer cells are very sensitive to disruption of the mitotic checkpoint – a so-called cellular mechanism that ensures proper separation of chromosomes during cell division.

“This allowed us to identify the unique vulnerabilities of aneuploid cells that we studied and characterized in depth at the molecular and cellular level,” says Ben-David.

“We have found that if you inhibit the proteins in these pathways, aneuploid cells are more susceptible to this interference than normal cells… therefore, they are attractive targets for drug discovery and drug development.”

The research has important implications for future cancer treatments and personalized medicine. Currently, several drugs that inhibit or delay the separation of chromosomes are in clinical trials, but researchers have not been able to identify which patients will or will not respond to them.

Ben-David’s study suggests that aneuploidy could help scientists determine an individual’s response to these drugs.

In addition, focusing on these chromosomal abnormalities could also lead to the development of more effective cancer treatments in the future, as doctors could test for aneuploidy and design treatment accordingly.

Dr Yael Cohen-Sharir, from the Department of Human Molecular Genetics and Biochemistry at Tel Aviv University, is the lead author of the study. Cohen-Sharir, who runs Ben-David’s lab, called the research revolutionary.

“Aneuploidy is very, very difficult to study,” she says. “It affects so many genes at once.”

Cohen-Sharir points out that the current study was conducted on cultured cells, not actual tumors, and further research needs to be done. The next step for the researchers, she says, is to try and replicate the results in mice.

As for Ben-David, he’s optimistic that harnessing the unique characteristics 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 cancer. body.

“Killing cancer cells is very easy: 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 that to his knowledge, this is the first time that aneuploidy has been systematically evaluated in human cancer cells.

“That’s why this is a major breakthrough,” he says.