In the early 1900s, the German zoologist Theodor Boveri discovered what is now a hallmark of cancer cells: their strong tendency to gain or lose entire chromosomes. The vast majority of all cancer cells — around 90 percent — are part of this club in varying degrees, making them aneuploid cells. Normal, healthy cells with the correct number of chromosomes are euploid. For almost all human cells, that means they are diploid — having two sets of 23 chromosomes (46 total).

“The discovery that chromosome missegregation is common in cancer cells is really as old as our understanding of cancer,” said Uri Ben-David, a cancer biologist at Tel Aviv University. “It actually comes even way before we knew what the chromosomes actually were — before people knew that DNA was even the hereditary material.”

Despite being known for over a century, aneuploidy in cancer remained widely understudied for decades. That’s partly because it’s such a challenging phenomenon to investigate, especially before major technological advances in genome sequencing came onto the scene. But research on the topic was also hampered by a longstanding debate about whether aneuploidy actually contributes to the development and progression of cancer, or if it just happens randomly as cancer cells mutate.

Over the past 15 years, scientists like the late Angelika Amon of the Massachusetts Institute of Technology and Rameen Beroukhim of the Dana-Farber Cancer Institute have finally begun to illuminate the direct role of aneuploidy in driving the formation and progression of tumorigenesis (1-3).

“One of the main issues is that it was easy to see that the chromosomes were screwed up, but these are really large-scale changes in these genomes. And so, to understand then specifically what that was doing was very hard,” said Beroukhim. “As the cost of sequencing decreased, we were able to generate a huge amount of data that allowed us to look into patterns much more accurately.”

Revealing the secrets of aneuploidies in cancer could also be key in the quest for better cancer treatments. “Understanding the biology is fundamentally important. … You can't fix a car until you really understand how an engine works,” said Beroukhim. More specifically, he noted that it might be possible to create drugs that reverse the effects of extra copies of genes due to aneuploidy, or to target mechanisms that prevent aneuploidy from happening in the first place.

Plus, targeting aneuploidy could offer a novel way to kill cancer cells while sparing healthy cells — since hardly any normal cells are aneuploid. “Cancer cells need to adapt to aneuploidy. They need to be able to cope with it in order to harness it and leverage it,” said Ben-David.

Leave nothing to chance

With the newest data on aneuploidy in cancer, it’s become clear that duplicating or removing whole chromosome arms does not happen at random. Rather, the aneuploidies found in cancer cells amplify or suppress certain genes to improve the fitness of the tumor.

Beroukhim’s team, in collaboration with Alison Taylor, now at Columbia University, recently developed a mathematical analysis method called BISCUT that successfully identified individual genes on chromosome arms that are commonly gained or lost in cancer (4). By analyzing over 10,000 tumors across 33 types of cancer, they found that cancer cells positively and negatively selected for mutations in these genes to favor the cancer’s growth and cell survival. “If it was just by chance, you would expect the break points to be all across the chromosome arm evenly,” said Taylor. But that’s not what they found. Instead, the BISCUT algorithm found specific break points where the rest of the chromosome arm was commonly deleted or duplicated.

The BISCUT method compares the changes expected by chance to actual observations for each chromosome arm. “Where the largest difference is, that probably means [cancer cells] really want to delete this region, or don't want to delete this region,” said Taylor. As one example, using BISCUT their team identified the WRN  gene — which is involved in DNA repair — as a potential tumor-suppressive gene. They found that cancer cells often get rid of one copy of this gene by deleting almost the entire short arm of one copy of chromosome 8.

“There's that age old question: What are these aneuploidies doing? Are they contributing to cancer, or are they just coming along for the ride? I think we really strongly addressed that question and have a series of strong arguments to say that they're contributing to cancer,” said Beroukhim.

Moving forward, Beroukhim added that the BISCUT method will continue to be extremely useful in the study of aneuploidy in cancer. “Now, we no longer have to worry about the arm as being just one whole arm, and we don't know how to tease it apart,” he said. “We have a framework with which we can detect the individual elements within those chromosome arms.”

Finding aneuploidy’s flaws

Ben-David and Stefano Santaguida, a molecular biologist at the University of Milan and the European Institute of Oncology, have also been developing new tools to better probe aneuploidy in cancer. Together, they seek to identify the vulnerabilities present in aneuploid cells that normal diploid cells don’t have — ideally, as a means to generate new therapeutic strategies.

Their research groups recently collaborated to create a model system that used genomic, transcriptomic, and proteomic profiling of cells with varying degrees of aneuploidy to extensively characterize their differences from diploid cells (5). This led the researchers to discover that aneuploid cells have higher baseline levels of DNA damage, which induces higher activity of DNA damage repair mechanisms. Ben-David said that this could explain why cancer cells with high degrees of aneuploidy are often resistant to chemotherapy; since the treatment works by inducing DNA damage, it may be less effective in cells that have highly active DNA repair mechanisms ready to counteract the effects.

The teams also found that the higher levels of aneuploidy in cancer cells means that they are more sensitive to drugs that target the mitogen-activated protein (MAP) kinase pathway, which is crucial in regulating cellular functions. “These two findings are actually functionally connected,” said Ben-David. “The activation of the MAP kinase signaling is required for the aneuploid cells’ ability to cope with elevated DNA damage. So, by inhibiting this pathway, you can also resensitize these cells to the DNA damage-inducing chemotherapies,” said Ben-David. As a result, they proposed combining chemotherapy with MAP kinase inhibitor drugs to achieve greater treatment potency.

As part of the same work, Ben-David and Santaguida’s teams also discovered that aneuploid cells show increased activity of several RNA and protein degradation pathways. They recently replicated this result in hundreds of cancer cell lines (6). Santaguida explained that aneuploid cells degrade proteins as a way to compensate for all of the extra mRNA and proteins produced as a result of having duplicated genes. “This is actually giving us a vulnerability [to target] because we are able to directly attack the main components of these pathways and try to exploit them to selectively kill them compared to diploid cells,” said Santaguida.

Drugs that attack protein degradation pathways already exist: proteasome inhibitors. But so far, they have often not succeeded in clinical trials for solid tumors. “Part of the reason that they failed is the lack of good biomarkers to stratify the patients that would respond from the patients who wouldn't respond,” said Ben-David. Their work demonstrates a possible path forward, as their paper showed that the levels of aneuploidy in multiple myeloma and pancreatic cancer cells were significantly correlated to patients’ responses to proteasome inhibitors.

There's a really nice community of people who are all really working on this and really dedicated to looking at different aspects of how to bring forward our understanding of aneuploidy’s role in cancer and how to target it therapeutically. 
– Alison Taylor, Columbia University

Ben-David and Santaguida agreed that the next steps are to translate these findings into benefits for cancer patients. Yet, Ben-David said that while it’s exciting that their research is identifying current cancer drugs that could work better in tumors with higher levels of aneuploidy, it also means it could be more difficult to attract pharmaceutical companies to pay for clinical trials with existing drugs. However, with more researchers now finally appreciating and studying the direct role of aneuploidy in driving cancer, therapeutics are closer than ever before. “There's a really nice community of people who are all really working on this and really dedicated to looking at different aspects of how to bring forward our understanding of aneuploidy’s role in cancer and how to target it therapeutically,” said Taylor.

Beroukhim added, “There's a ton of complexity in [the cancer genome] and aneuploidy is the maybe most important component of that. And we still don't really understand that, and so there's still a lot of work to do.”

References

1. Stopsack, K.H. et al.  Aneuploidy drives lethal progression in prostate cancer. Proc Natl Acad of Sci USA  116, 11390–11395 (2019).
2. Beroukhim, R. et al.  The landscape of somatic copy-number alteration across human cancers. Nature  463, 899–905 (2010).
3. Williams, B.R. & Amon, A. Aneuploidy: Cancer’s Fatal Flaw? Cancer Res  69, 5289–5291 (2009).
4. Shih, J. et al.  Cancer aneuploidies are shaped primarily by effects on tumour fitness. Nature  619, 793–800 (2023).
5. Zerbib, J. et al.  Human aneuploid cells depend on the RAF/MEK/ERK pathway for overcoming increased DNA damage. Nat Commun  15, 7772 (2024).
6. Ippolito, M.R. et al.  Increased RNA and Protein Degradation Is Required for Counteracting Transcriptional Burden and Proteotoxic Stress in Human Aneuploid Cells. Cancer Discov  14, 2532–2553 (2024).