An international research team, co-led by the Technische Universität Kaiserslautern, has identified a universal vulnerability in most cancer cells that could help lead to drugs that target tumors regardless of cancer type.
Cancer cells with an abnormally high number of chromosomes appear to rely on a particular protein for cell division and largely die when the protein is blocked, researchers in Germany, Israel, Italy and the US report in the journal Nature. Since more than 90 percent of tumors, regardless of tissue type, contain extra chromosomes, this protein could present an effective target for treating a wide range of cancers.
“We think we have found a possible vulnerability of cancer cells with abnormal chromosome numbers,” says Dr. Zuzana Storchová, a professor of molecular genetics at the Technische Universität Kaiserslautern (TUK) in Germany, and a co-senior paper author.
Normal, healthy cells have 46 chromosomes, but malignant tumors often consist of highly abnormal cancer cells that can have deviant chromosome numbers, usually ranging between 60 to 90 chromosomes. They are called aneuploid cancer cells. For a long time, researchers thought aneuploidy was a side effect of cells turning cancerous, but in the last 15 years, more suspect this might be one of the driving forces of cancer. Finding a common feature associated with this aberrant number of chromosomes could be critical for targeting cancer regardless of where it develops in the Body.
Cancer’s Achilles heel
Storchová and collaborators conducted extensive experiments with nearly 1,000 cell lines from human cancer patients and model cancer cells cultured in the lab. Ultimately, they identified a protein, called KIF18A, as essential for aneuploid cancer cells to proceed through a key part of cell division, called chromosome segregation. Normally, if there are too many errors made while segregating chromosomes, the so-called spindle assembly checkpoint is activated and delays cell division until the errors are corrected. Aneuploid cancer cells often keep going, despite the extra chromosomes, and commit more errors during mitosis. The researchers found that when the checkpoint is not functioning correctly and unable to stop division, aneuploid cancer cells appear to commit so many errors, they are unable to survive. Additionally, they found that if the KIF18A protein is blocked, those cells are more likely to die than cells with a normal number of chromosomes.
“We were able to apply state-of-the-art tools to an age-old question in cancer biology – what is the Achilles heel of chromosome number changes in cancer?” says Dr. Uri Ben-David, an assistant professor at Tel Aviv University in Israel and co-senior paper author. “I'm excited that our findings, if they hold true in a clinical setting, may have several therapeutic implications for the care of cancer patients.”
KIF18A is a kinesin motor protein that binds to and regulates the mitotic spindle, which is a molecular structure that enables correct chromosome division. The researchers don’t yet know exactly what KIF18A does differently in aneuploid cells than in normal cells, but they theorize it somehow helps the dividing cell physically accommodate the abnormally high number of chromosomes. Through cell imaging, they see that the mitotic spindle has a different shape in the aneuploid cells than in normal cells. This will be an area of further research.
“Right now, there are no inhibitors available to block KIF18A in human cells, but if we can understand the mechanism better, then we could maybe develop chemical molecules that could target KIF18A itself or the processes related to it,” Storchová says.
Storchová studies how extra chromosomes affect cell physiology, function and development of cancer. Several years ago, she and her team observed KIF18A appeared essential for model versions of aneuploid cancer cells, but at the time, there was no publicly available data to confirm the finding applied to human cancers. She put the finding aside, until 2017, when she met Ben-David at a conference. During an informal conversation, he explained he was screening nearly 1,000 cancer cell lines from patients, searching for a common vulnerability. She mentioned her work on KIF18A and when he reviewed his data, he also found the protein was showing up as highly important for these cells. Further analysis, conducted over the past few years, helped them rule out other proteins and genes and prove that KIF18A is the essential component.
“This reminds us how important these informal discussions between scientists are,” Storchová says. “Also, it shows how complex science can be, and sometimes one needs to be ready for the long run. It took some time before we had more evidence to show this is not just a random observation valid in our models, but is a more general principle.”
Ben-David agreed, highlighting the importance of basic research, which can take a long time before leading to medical breakthroughs.
“Clinical discoveries always stand on the shoulders of basic science discoveries,” he says. “Our results are all based on cell cultures, and so we do not know yet how well they will translate to actual human patients. However, these results open very promising research directions, which have the potential to ultimately affect patients' care.”
Research in COVID times
The coronavirus pandemic posed a major challenge for finishing the project because labs were required to close at various times. First paper author Yael Cohen-Sharir finished key experiments at Tel Aviv University two days before Israel went into a month-long lockdown. The research team, which also included the University of Milan and European Institute of Oncology in Italy; and the Broad Institute of Massachusetts Institute of Technology and Harvard University, the Dana Farber Cancer Institute and the University of Vermont in the US, helped each other, with whoever was open conducting necessary tests. “At any given time point we had at least one lab somewhere in the world that was open and willing to help us out,” Ben-David said.
Storchová in particular applauded TUK PhD student Sara Bernhard and undergrad Lisa-Marie Stautmeister for “absolutely heroic work” to conduct additional measurements required for the paper to be finished during the pandemic.
Prof. Dr. Zuzana Storchova
Tel.: +49 (0)631-205-3250
Dr. Uri Ben-David
Assistant Professor (Senior Lecturer)
Department of Human Molecular Genetics & Biochemistry
Faculty of Medicine, Tel Aviv University
Yael Cohen-Sharir et al., “Aneuploidy renders cancer cells vulnerable to mitotic checkpoint inhibition”, DOI: 10.1038/s41586-020-03114-6.