Scientists Uncover Key Driver of Treatment-Resistant Cancer
These images show the beginnings of chromothripsis in colorectal cancer cells. The N4BP2 enzyme (green) infiltrates a micronucleus (zoomed in square selections), where it induces DNA damage (red). Blue represents the main cell nucleus.
Credit: UC San Diego Health Sciences
This is reported in a research paper in Science by researchers at the University of California, San Diego (UC San Diego).
The researchers discovered an enzyme responsible for breaking up a chromosome in cancer cells and rearranging it into a scrambled version, enabling the tumour to evolve rapidly. The process is quite simple and closely mimics evolution by natural selection, or the development of antibiotic resistance in bacteria. Shuffling genes in this way increases the likelihood that a small number of cancer cells will survive the treatment aimed at destroying them. The tumour then regrows from these resistant cells, producing a treatment-resistant cancer.
This ability, known as chromothripsis, is found in about 24% of human cancers.
The key to this process is the protein enzyme N4BP2, and the complex, specified gene that produces it. The process begins when an error in DNA replication causes individual chromosomes to become trapped inside tiny, fragile structures called micronuclei. When these micronuclei burst, the chromosome is exposed to nucleases — enzymes capable of breaking DNA.
Within the ID creationist paradigm, there are no such things as mistakes: everything works exactly as it was designed to work. So we are left to assume that these fragile micronuclei, with their entrapped chromosomes, are a deliberate design feature.
The researchers showed that N4BP2 is uniquely capable of entering micronuclei and breaking the trapped chromosome.
To test the hypothesis that N4BP2 is the culprit, they eliminated it in brain cancer cells and observed a reduction in chromothripsis. They then introduced it into healthy cell nuclei and found that it caused chromosomes to break even in otherwise normal cells.
This is, of course, just as much compelling evidence of intelligent design as anything traditionally cited by ID creationists as proof of an intelligent designer. By contrast, the theory of evolution provides an explanation with none of the problems that force creationists to retreat into contradictory theology, Bronze Age origin myths, and appeals to ‘mystery’.
Background^ Cancer as Evolution in Fast Forward. One of the most uncomfortable facts for advocates of Intelligent Design is that cancer is among the clearest demonstrations of evolution by natural selection happening in real time.The research and its wider implications for understanding how cancers develop resistance to treatments through an evolutionary process are explained in an article in UC San Diego Today.
A tumour is not a single uniform entity, but a vast population of cells, often numbering in the billions. As these cells divide, they accumulate mutations and genetic rearrangements, producing variation within the tumour — exactly the raw material required for evolution.
When a patient undergoes chemotherapy or targeted treatment, the therapy acts as an intense selective pressure. Most cancer cells may be destroyed, but any rare cell carrying a mutation that allows it to survive will continue dividing. The tumour then regrows, but now it is composed largely of treatment-resistant descendants.
This process is directly analogous to antibiotic resistance in bacteria: the treatment does not *create* resistance, it simply selects for the variants already best able to survive.
Far from being mysterious, cancer’s ability to evolve is precisely what evolutionary theory predicts — and one of the strongest reminders that natural selection operates wherever there is replication, variation, and survival advantage.
By insisting that evolution doesn't happen and that genetic change can only occur under the control of their putative intelligent designer, creationists unwittingly create an argument for their god's culpability in cancers and the suffering they cause.
Scientists Uncover Key Driver of Treatment-Resistant Cancer
UC San Diego scientists discover enzyme responsible for scrambling cancer genomes; results could enable new treatments for the most aggressive cancers.
University of California San Diego researchers have discovered the enzyme responsible for chromothripsis, a process in which a single chromosome is shattered into pieces and rearranged in a scrambled order, allowing cancer cells to rapidly evolve and become resistant to treatment. Since its discovery more than a decade ago, chromothripsis has emerged as a major driver of cancer progression and treatment resistance, but scientists haven’t learned what causes it. Now, UC San Diego scientists have solved this longstanding mystery in cancer biology, opening up new possibilities for treating the most aggressive cancers. The results are published in Science.
Chromothripsis is just one of several mechanisms cancer cells use to evolve and resist therapy, but it stands out because of its scale. Instead of accumulating mutations gradually, chromothripsis can generate dozens to hundreds of genomic alterations in a single catastrophic event, accelerating cancer evolution dramatically. It is also remarkably common: researchers estimate that approximately one in four human cancers shows evidence of chromothripsis, and for some tumors the rate is even higher. For example, virtually all osteosarcomas — an aggressive bone cancer — display chromothripsis, and many brain cancers show unusually high levels as well.
This discovery finally reveals the molecular ‘spark’ that ignites one of the most aggressive forms of genome rearrangement in cancer. By finding what breaks the chromosome in the first place, we now have a new and actionable point of intervention for slowing cancer evolution.
Professor Don Cleveland, Ph.D., senior author
Department of Cellular and Molecular Medicine
University of California at San Diego
La Jolla, CA, USA,
Chromothripsis occurs after errors in cell division cause individual chromosomes to become trapped inside tiny, fragile structures called micronuclei. Once a micronucleus bursts, its chromosome is left exposed and vulnerable to nucleases, enzymes that are capable of breaking DNA apart.
Before now, scientists didn’t know which specific nuclease triggers chromothripsis, making it impossible to target the process with cancer treatments.
These images show experiments used by the researchers to prove that the N4BP2 enzyme causes chromothripsis. In the top row, the enzyme was added directly to cell nuclei, resulting in DNA damage (red). On the bottom, the enzyme was confined to the space outside the nucleus, and DNA damage did not occur (no red signal).Credit: UC San Diego Health Sciences.
To answer this question, the researchers used an imaging-based screening technique to comb through all known and predicted human nucleases and observe how they affect human cancer cells in real time. Their analysis found one enzyme, called N4BP2, that is uniquely capable of entering micronuclei and breaking DNA apart.
To prove that N4BP2 actually causes chromothripsis, the researchers then eliminated the enzyme in brain cancer cells. They found that eliminating N4BP2 sharply reduced chromosome shattering, while forcing N4BP2 into the cell nucleus caused intact chromosomes to break, even in otherwise healthy cells.
These experiments showed us that N4BP2 isn’t just correlated with chromothripsis. It is sufficient to cause it. This is the first direct molecular explanation for how catastrophic chromosome fragmentation begins.
Dr Ksenia Krupina, Ph.D., first author
Department of Cellular and Molecular Medicine
University of California at San Diego
La Jolla, CA, USA.
The researchers also analyzed more than 10,000 human cancer genomes across many cancer types, finding that tumors with high N4BP2 expression showed significantly more chromothripsis and structural rearrangements. These cancers also exhibited elevated levels of extrachromosomal DNA (ecDNA) —circular DNA fragments that carry cancer‑promoting genes and are strongly linked to treatment resistance and aggressive growth.
Because tumors that contain ecDNA tend to be among the most difficult to treat, ecDNA has gained widespread scientific attention in recent years, including being named one of the Cancer Grand Challenges by the National Cancer Institute and Cancer Research UK. The new UC San Diego findings reveal that ecDNA is not an isolated phenomenon, but rather a downstream consequence of the much broader phenomenon of chromothripsis. By placing N4BP2 at the very start of this process, the study identifies a new molecular entry point for understanding — and potentially controlling — the most chaotic forms of genome instability in cancer.
Understanding what triggers chromothripsis gives us a new way to think about stopping it. By targeting N4BP2 or the pathways it activates, we may be able to limit the genomic chaos that allows tumors to adapt, recur and become drug‑resistant.
Professor Don Cleveland, Ph.D.
Additional coauthors of the study include Alexander Goginashvili, Michael W. Baughn, Stephen Moore, Christopher D. Steele, Amy T. Nguyen, Daniel L. Zhang, Prasad Trivedi, Aarti Malhotra, David Jenkins, Andrew K. Shiau, Yohei Miyake, Tomoyuki Koga, Shunichiro Miki, Frank B. Furnari and Ludmil B. Alexandrov, all at UC San Diego and Jonas Koeppel and Peter J. Campbell of the University of Cambridge and the Wellcome Trust Sanger Institute.
Publication:
Once again, what this research highlights is that the very mechanisms ID creationists insist are evidence of purposeful design are, in reality, also the mechanisms by which cancers adapt, survive, and kill. Chromothripsis, micronuclei rupture, and enzymes such as N4BP2 are not curiosities on the fringes of biology: they are part of the messy, contingent machinery that allows tumours to evolve rapidly under selective pressure.
If complexity and “specified information” are taken as proof of an intelligent designer, then that designer must also take responsibility for the elaborate genetic systems that enable treatment resistance, relapse, and suffering. Creationists cannot logically claim the immune system as evidence of benevolent design while pretending the evolutionary ingenuity of cancer is somehow an unfortunate accident outside the same framework.
By contrast, evolution requires no theological evasions. Cancer is simply natural selection operating at the cellular level, exploiting vulnerabilities and genetic variation in exactly the way evolutionary theory predicts. The real world is not a showcase of perfect engineering, but a landscape shaped by history, compromise, and relentless selection — sometimes with lethal consequences.
And every new discovery like this makes the creationist appeal to “design” look less like an explanation, and more like an attempt to avoid one. Once again, reality insists on evolution, no matter how loudly creationism protests.
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