Cancers with an Exceptional Cause – The Scientist

Cancers typically arise when cells accumulate mutations in their DNA that prevent them from keeping cell division in check.1 However, for some tumor types, researchers have struggled to find mutations, leading scientists to question their causes.2 Now, in a study published in Nature, researchers found that short-lived epigenetic changes can permanently alter gene expression and trigger cancer.3 While most cancers develop following mutations, their findings suggest that a few tumor types might deviate from this rule.

For years, Giacomo Cavalli, a geneticist at the French National Centre for Scientific Research, and his colleagues have studied the role that epigenetic factors called Polycomb proteins play in cancer.4 These proteins form complexes that wind up chromatin and switch off genes that promote cell division. The team previously found that mutations in Polycomb factors cause chromatin unraveling, which cascades into cell proliferation and cancer initation.5 They wondered whether they could achieve the same effect by temporarily switching Polycomb genes off.

To test their hypothesis, they turned to the fruit fly, Drosophila melanogaster; the species has only one copy of each gene involved in the Polycomb machinery, making it easier to disrupt the system. Polycomb proteins play key roles during development by influencing the timing of cell differentiation. Cavalli and his team studied the impact of losing this epigenetic control on early, larval structures called imaginal discs. Using a temperature-sensitive RNA interference system, they exposed the discs to warmer temperatures for 24 hours, which temporarily turned off the Polycomb genes for two days.

They very nicely showed that with this transitory system they could switch off this development gene briefly, switch it back on, and that was enough to trigger tumorigenesis, said Douglas Hanahan, a cancer biologist at the Swiss Federal Institute of Technology Lausanne who was not involved with the work.

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To ensure that genetic mutations didnt trigger these cancers, the team sequenced the cancer cells alongside healthy controls. You do have mutations, Cavalli said, but there is no difference in the quantity of the mutational events in the cancer samples compared to the control samples.

To confirm that these mutations did not kickstart the cancers, the team tracked the position of tumor cells in the imaginal discs. They hypothesized that if mutations gave rise to a cancer, they would have started with a single troublemaker cell whereas epigenetic reprogramming would have stirred up rebellion of the whole tissue. To spot fast-dividing tumor cells, they stained the imaginal discs with 5-ethynyl-2-deoxyuridine (EdU), a dye that takes the place of thymine during DNA replication.6 EdU was ubiquitous throughout the imaginal discs, pointing to tissue-wide epigenetic reprogramming as the cancer culprit.

Cavallis team found that temporarily knocking down Polycomb factors fired up genes that they typically repress. This led to a surge in Janus kinase/signal transducers and activators of transcription (JAK-STAT) signaling, which promotes cell proliferation.7 JAK-STAT activation also caused a domino effect, flipping the switch on other genes linked to cancer. This included booting up the zinc finger homeodomain-1 gene, which suppresses developing cells from differentiating and ultimately slows down growth.8

According to Cavalli, the study raises questions about how often epigenetic alterations drive tumor formation. It can be more common than we think, Cavalli said. When we sequence cancers and find mutations, we typically do so when the cancer is already developed. However, its possible that epigenetic forces transformed the initial cells, he suggested. Indeed, this might apply to some brain cancers in children.9 There is no evidence for a blizzard of mutations in these pediatric tumors, and yet there are tumors, Hanahan said, adding that these cancer types could be fertile grounds to explore epigenetic triggers in humans.

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Researchers arent sure which factors trigger these short-lived, cancer-causing epigenetic changes. Inflammation is a major promoter of tumor initiation, Hanahan said. Immune cells might secrete a milieu of chemicals signals that disrupt epigenetic control of gene expression within cells and prompt cancers, he suggested.

Looking ahead, Cavalli aims to move away from the fruit fly to study epigenetic drivers in mammalian models that have an immune response and vasculatureboth of which influence cancer evolutionthat better reflect those of humans.

Cavalli noted that some researchers are developing epigenetic cancer therapies, which aim to reverse cancer cells instead of killing them.10 Further research into the role of epigenetics in tumor initiation could help drug developers work out how to subdue these long-overlooked cancer drivers.

1. Hanahan D. Hallmarks of cancer: New dimensions.Cancer Discov. 2022;12(1):31-46. 2. McDonald OG, et al. Epigenomic reprogramming during pancreatic cancer progression links anabolic glucose metabolism to distant metastasis.Nat Genet. 2017;49(3):367-376. 3. Parreno V, et al. Transient loss of Polycomb components induces an epigenetic cancer fate.Nature. 2024;629(8012):688-696. 4. Parreno V, et al. Mechanisms of Polycomb group protein function in cancer.Cell Res. 2022;32(3):231-253. 5. Loubiere V, et al. Coordinate redeployment of PRC1 proteins suppresses tumor formation during Drosophila development.Nat Genet. 2016;48(11):1436-1442. 6. Flomerfelt FA, Gress RE. Analysis of cell proliferation and homeostasis using EdU labeling. In: Bosselut R, S. Vacchio M, eds. T-Cell Development.Method Mol Biol. 2016;1323:211-220. 7. Zoranovic T, et al. Regulation of proliferation, cell competition, and cellular growth by the Drosophila JAK-STAT pathway.JAK-STAT. 2013;2(3):e25408. 8. Leatherman JL, DiNardo S. Zfh-1 controls somatic stem cell self-renewal in the Drosophila testis and nonautonomously influences germline stem cell self-renewal.Cell Stem Cell. 2008;3(1):44-54. 9. Jenseit A, et al. EZHIP: A new piece of the puzzle towards understanding pediatric posterior fossa ependymoma.Acta Neuropathol. 2022;143(1):1-13. 10. Miranda Furtado CL, et al. Epidrugs: Targeting epigenetic marks in cancer treatment. Epigenetics. 2019;14(12):1164-1176.

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Cancers with an Exceptional Cause - The Scientist