A study led by researchers at Memorial Sloan Kettering Cancer Center (MSK) has revealed a surprising connection between chromosomal instability and epigenetic changes in cancer cells. Both of these alterations are known hallmarks of cancer, particularly advanced and drug-resistant forms. The research, published in the journal Nature, not only opens up new possibilities for cancer treatment but also provides new areas for further exploration and study.
Chromosomal instability refers to changes in the number of chromosomes carried by each cancer cell, while epigenetic alterations change which genes are turned on or off in a cell without modifying the cell’s DNA code. The study was initiated by a graduate student, Albert Agustinus, who became curious about the relationship between these two phenomena. He initiated a collaboration between the labs of Samuel Bakhoum, MD, Ph.D., and Yael David, Ph.D., both experts in their respective fields at MSK.
Through their research, the team discovered that chromosomal instability and epigenetic changes work together to create variations among individual cancer cells within the same tumor. This variation increases the survival and resistance of the cancer cells to treatment. The findings suggest that mutations in the genes encoding epigenetic-modifying enzymes are not necessary for epigenetic abnormalities to occur. The ongoing chromosomal instability is sufficient to trigger these changes, which explains why advanced, drug-resistant cancers often exhibit both chromosomal instability and epigenetic abnormalities.
The researchers also found that the presence of micronuclei, small extra nuclei in cells, is a signal of chromosomal instability. Micronuclei contain genetic material and their burst leads to further problems and disruption of chromatin organization, resulting in ongoing epigenetic dysregulation. The repeated formation and reincorporation of micronuclei over many cell division cycles lead to the accumulation of epigenetic changes and greater variation between cancer cells within a tumor. This variation is associated with resistance to treatment.
The research team conducted sophisticated experiments to isolate micronuclei and analyze the changes occurring within them compared to the cells’ primary nuclei. They observed patterns of histone modification, changes to the structure of DNA in relation to gene expression. The researchers discovered that the micronuclei had a greater number of accessible promoter regions, indicating increased gene transcription activity.
The study has significant clinical implications. Epigenetic changes are reversible, and several classes of drugs have been developed to target them. The findings suggest that chromosomal instability and the presence of micronuclei could be used as biomarkers to identify patients who may benefit from epigenetic modifying drugs. This research also raises the possibility of treating chromosomally unstable cells with epigenetic modifying therapies.
The MSK study findings were supported by another research team at Harvard University and the Dana-Farber Cancer Institute, further confirming the relationship between chromosomal instability and epigenetic changes.
Overall, this research not only sheds light on the mechanisms underlying cancer development and drug resistance but also offers potential new treatment options for patients. The unexpected connection between chromosomal instability and epigenetic changes opens up new avenues for further investigation and clinical application.