Experiment on flies casts doubt on decades-old theory about the origin of cancer | Health and wellness

More than forty years ago, it was discovered that cancer arises from the accumulation of persistent genetic mutations within normal cells. These changes cause cells to multiply uncontrollably or survive selfishly when their presence is harmful to the organism they are meant to serve. For decades, this idea has made finding the altered genes that most commonly cause tumors an important part of the fight against cancer; accurately diagnose the type of cancer in each patient or develop drugs that block the activity of these harmful genes.

It has also been known for some time that, as well as the role of genes in the development of living things, a series of chemical tags, or proteins, that are added to inherited DNA are important. These modifications, called epigenetic because they are added as interpretations of the genome, cause the same instruction book to be read differently and produce different results. For example, in bees, larval feeding has epigenetic effects with dramatic consequences. Depending on their diet, individuals with the same genome can become a queen, who lives for three years and can reproduce, or a sterile worker who dies after a few weeks.

Epigenetic changes that can reprogram the activity of normal genes have already been linked to some types of cancer, and there are epigenetic drugs used to fight tumors, mainly of the blood. But it was unknown whether these mechanisms themselves could cause cancer. Now a team from the CNRS Institute of Human Genetics and the University of Montpellier is publishing a paper in the journal. Nature which challenges the idea that tumors arise only due to constant mutations.

Scientists led by Giacomo Cavalli and Anne-Marie Martinez used fruit flies (Drosophila melanogaster) to see whether a temporary modification of their gene expression that does not result in permanent changes in the DNA sequence can cause a tumor. To test this, they caused a transient disruption of a group of Polycomb proteins, an epigenetic regulation system that we share with flies. This system is fundamental for proper embryonic development or deciding whether a cell will become a muscle cell or an eye cell. In humans, mutations in the Polycomb genes are associated with several types of cancer, and in an experiment, manipulation of them caused tumors in the eyes of flies. When scientists repaired the broken system, the effects of the epigenetic changes were delayed by the fly’s cell division, and the cancer continued to grow unchecked.

Although the research is basic biology and uses an insect as a model, it is a first step that could change part of our understanding of cancer. According to current theory, it is initiated by the accumulation of DNA mutations that are largely random and “essentially due to bad luck,” Cavalli explains. However, over the past decade, it has been observed that many epigenetic components are disrupted in many types of cancer, and in some of them, driver mutations are absent or very few are detected. Moreover, Cavalli notes that “in cancers that exhibit driver mutations, metastases typically have few or no additional mutations compared to the primary tumor, but have consistent epigenetic changes (in many parts of the genome).” . The study, published today in Nature This also proves that cancer can arise from a simple epigenetic disorder, without DNA mutations.

This mechanism may explain the growth of tumors at an early age – a disturbing phenomenon that has no explanation. According to Cavalli, “it is unlikely that this increase is due to increased mutagenicity and therefore it is possible that diet and exposure to weakly mutagenic pollutants such as bisphenol A or arsenic may be associated with this increase.”

From left to right: Anne-Marie Martinez, Lorian Fritsch, Bernd Schuttengruber and Giacomo Cavalli, authors of the study.

Manel Esteller, a professor of genetics at the University of Barcelona, ​​appreciates the work but cautions about its limitations. “This is a fly model, and flies usually don’t have tumors,” he notes. “There are people who don’t talk about tumors in flies, but rather cell proliferations, something like fibroids,” he gives an example. “And the fly lacks many of the epigenetic mechanisms that humans have, such as DNA methylation,” he adds. “This is interesting work, but its applicability in the context of human tumors is questionable,” he concludes.

Re-educate cells

Esteller, however, emphasizes the importance of epigenetic changes in cancer. “We know that there are human tumors that do not have genetic changes and are still developing. This is especially the case with childhood tumors and brain tumors, which are almost purely epigenetic, and some of them do not show any mutations,” he continues. There are now epigenetic cancer treatments for leukemia, lymphoma or sarcoma, but in solid tumors such as lung cancer, the genetic damage is more significant and such solutions are more difficult to apply.

Cavalli believes that the discovery of these mechanisms, which trigger tumors without changes in DNA, allows us to think about new methods of treating these diseases that would be a kind of re-education. In these early stages of tumor development, there are no mutations, and although epigenetic changes have rendered them out of control, the cells retain the necessary information for normal differentiation. Deactivation of the Polycomb system causes genetic changes detrimental to cell differentiation, which can be reversed.

“In the case of humans, treatments are usually aimed at killing tumor cells, but is it possible, at least for all those cancers that have few or no mutations, to train the cells to differentiate properly and stop excessive proliferation, instead of try to kill them? asks Cavalli. This would avoid the negative consequences of current treatments, which, by eliminating many tumor cells, put selective pressure on those who are able to resist treatment, which after some time leads to relapses with a more virulent version of the tumor that is more difficult to treat.

It remains to be tested whether this paradigm shift can be applied to understanding the occurrence of cancer in humans. First, the CNRS team will use laboratory models that mimic organs, such as organoids or gastruloids, which recapitulate the first stages of embryonic development. If they can prove that brief changes in epigenetic signals can cause long-term disruptions in cell differentiation, such as those associated with cancer, they will continue to advance and develop these types of experiments in mice. Eventually, people will arrive.

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