New Insights into Cancer Mechanism: The Role of Extrachromosomal Circular DNA
Recent studies published in the journal Nature have unveiled the aggressive role of extrachromosomal circular DNA (ecDNA) in cancer progression, based on research involving 15,000 patients across 39 types of tumors. Scientists have identified ecDNA as a circular, dissociative DNA molecule found within the cytoplasm of various cancer cells, believed to amplify oncogenes—genes that have undergone mutations leading to cancer. These findings advocate that ecDNA is not only pivotal in cancer progression but also significantly contributes to drug resistance.
Led by Professor Paul Mischel from Stanford University, the international research group eDyNAmiC has received a notable $25 million grant from public institutions in the UK and the US to further explore the mechanisms of ecDNA. Mischel highlighted the team's progress, stating, "We are on the verge of understanding a common and aggressive mechanism that drives the onset and evolution of cancer."
Historically, it was believed that only about 2% of tumors contained significant amounts of ecDNA. However, Mischel's team demonstrated back in 2017 that ecDNA is more widespread than previously thought and plays a crucial role in not only cancer development but also treatment resistance and metastasis. Last year, they revealed that the presence of ecDNA facilitates the transformation of precancerous cells into cancerous ones.
The research has further provided insights into the genetic backgrounds and mutations associated with ecDNA's emergence and proliferation. One remarkable finding is that during cell division, ecDNA is continuously segregated in units of several circles to daughter cells. This phenomenon challenges Gregor Mendel's principle of independent gene distribution, which was established through his studies with pea plants. Mischel uses a poker analogy to explain this: “Cancer cells that receive a good hand of cards gain an advantage, and we have uncovered the mechanism by which they achieve it.”
Crucially, the research has also identified a potential vulnerability in this advantageous process for cancer cells. There exists a tension between transcription (the process of copying DNA into RNA) and cell replication. When these two processes encounter a conflict, cell replication halts and internal checkpoints are activated to pause cell division until the issue is resolved. One of the articles published details how inhibiting the activity of a protein called CHK1 not only leads to the death of tumor cells containing ecDNA in laboratory settings but also prompts tumor regression in mice models of stomach cancer. This CHK1 inhibitor is currently in the early stages of clinical trials.
As scientists continue to delve deeper into the intricacies of ecDNA and its relationship with cancer biology, these discoveries mark significant strides towards better understanding the complexities of cancer mechanisms and developing targeted therapies.
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