How Cancer Cells Tolerate Chromosomal Imbalance

A hallmark of cancerous cells is an abnormal number of chromosomes or chromosome arms, known as aneuploidy. While aneuploidy is detrimental to regular cells, it occurs in as many as 90% of tumors. How cancer cells tolerate this chromosomal imbalance has remained unclear.

To better understand how these cells function, the laboratory of Yansheng Liu, PhD, associate professor of pharmacology, uses mass spectrometry to measure the amounts of proteins in cells, as well as how they're produced and removed. Through this technique, Liu’s team previously discovered that cells with too many chromosomes degraded excess proteins at higher rates. The findings supported the predominant view in biology research that cells maintain the correct balance of proteins primarily by adjusting the rate at which they break proteins down.

Liu is hopeful that a deeper understanding of these mechanisms could offer new insights into treating cancer.

Now, in a new Molecular Cell study, Liu’s team looked at how cells function when chromosomes are missing. To their surprise, they found that protein degradation rates overall remained the same as normal cells. Rather, cells selectively increased synthesis rates of the proteins encoded by the missing chromosome, challenging current conceptions.

“We found a new mechanism in which cells are increasing the speed of producing certain proteins to cope with the loss of a chromosome,” says Liu, who is also a member of Yale Cancer Center and the Yale Cancer Biology Institute at Yale's West Campus. Revealing the fundamental mechanisms underlying cancer biology could lead to new clinical applications.

Chromosomes are the tiny packages that store cellular DNA; and DNA holds the instructions for producing proteins. “Proteins are a major player in many biological and biochemical pathways,” says Liu. “So, it is essential for the cell to keep proteins at the right concentration, absolutely and relatively.”

When cells have extra chromosomes, however, that leads to too many proteins.

During Liu’s postdoctoral fellowship at ETH Zurich, his team studied cells with human trisomy 21, a genetic condition also known as Down syndrome that is associated with an extra copy of chromosome 21. The researchers used mass spectrometry to measure the degradation rates of proteins, finding that cells with trisomy 21 could increase the degradation of proteins associated with the extra chromosome.

In the context of cancer, many cells are associated with both extra and missing chromosomes. And, in some cases, the cancerous cells gain or lose only part of a chromosome. Each chromosome is divided into two “arms”—a shorter arm called “p” and a longer arm “q.” Over 60% of lung squamous cell carcinoma tumors, for example, are associated with an extra q arm on chromosome 3. And in nearly 80% of these tumors, chromosome 3 is missing the p arm.

In Liu’s team’s latest study, they wanted to understand how cancer cells function when they’re missing parts of a chromosome. One way cells might maintain the correct balance of proteins, they predicted, was through reducing the break down of those associated with the missing chromosome. Or, on the other hand, the cells might increase the degradation of all unaffected proteins in order to maintain relative balance.

Through a collaboration with the laboratory of Alison M. Taylor, PhD, Florence Irving Assistant Professor of Pathology and Cell Biology at the Herbert Irving Comprehensive Cancer Center at Columbia University, the team created models of lung epithelial cells—the cells that form the organ’s protective barrier. Using CRISPR gene-editing technology, the researchers removed the p arm of chromosome 3 from these cells. They also obtained another subset of cells with a q arm added to chromosome 3.

Using similar techniques to the trisomy 21 study, but with improved precision and sensitivity, the researchers analyzed changes in protein composition in three types of cells—normal cells, 3p loss cells, and 3q gain cells. In the cells with an extra 3q arm, the findings were as expected, Liu says—the cells increased the degradation of proteins associated with 3q as an attempt to keep the relative protein concentrations.

In cells lacking a 3p arm, however, the researchers discovered that both of their hypotheses were wrong. There were no significant changes in rates of any protein degradation, up or down. Rather, to their surprise, the cells accelerated the synthesis of proteins associated with 3p in certain contexts.

“Many in the field currently assume that degradation explained how cells maintain proteostasis, or protein balance,” Liu says. “But we actually reported with very clear data that upregulated protein synthesis is the key for how cells tolerate loss-type aneuploidy.

"Because we had an unexpected result from our mass spectrometry analysis, we validated it using another method,” Liu adds. “Our protein-based measurements and RNA-based measurements both tell us that selective protein synthesis regulation, not degradation, drives the buffering of the 3p loss-type aneuploidy.”

Through additional analyses, the researchers also discovered that proteins associated with 3p had greater thermostability—in other words, the melting points were significantly higher. The finding points to a potential biological mechanism underlying how cells adapt to loss-type aneuploidy.

The study reminds Liu of the teachings of ancient Chinese philosopher Laozi, who once said, “The way of Heaven is to diminish superabundance and supplement deficiency.” The model cells paralleled this philosophy—they supplemented deficient proteins to maintain balance.

Liu is hopeful that a deeper understanding of these mechanisms could offer new insights into treating cancer. Targeting the proteins differentially impacted by aneuploidy, for example, might help lead to new therapeutics.

“Cancer aneuploidy biology is a very popular area within cancer research,” he says. “By revealing the fundamental rules, we can learn how these rules may be translated to some clinical applications.”

Reference: Di Y, Li W, Castellano JJ, et al. Divergent proteome tolerance against gain and loss of chromosome arms. Molecular Cell. 2025;85(22):4268-4278.e6. doi: 10.1016/j.molcel.2025.10.023

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