Welcome to Study of the Week from Patient Worthy. In this segment, we select a study we posted about from the previous week that we think is of particular interest or importance and go more in-depth. In this story we will talk about the details of the study and explain why it’s important, who will be impacted, and more.
If you read our short form research stories and find yourself wanting to learn more, you’ve come to the right place.
This week’s study is…
Genome-wide CRISPR screen identifies noncanonical NF-κB signaling as a regulator of density-dependent proliferation
We previously published about this research in a story titled “Oncology Researchers Are Beginning to Focus on Ways to Stop Uncontrolled Cancerous Cell Division,” which can be found here. The study was originally published in the research journal eLife. You can view the full study text here.
The team of researchers in this study were affiliated with the Vanderbilt University.
In practically all of its known forms, cancer is characterized as a disease which involves abnormal, uncontrolled cell proliferation and growth. These abnormal cells have the potential to spread or invade other areas of the body beyond their point of origin. While the risk factors and causes of cancer can vary widely, the precise mechanism that triggers the abnormal cell growth observed in cancer still remains largely unknown. The scientists in this study sought to learn more about this process. In order to do so, they tapped into the special abilities of CRISPR, technology that allows for selective gene editing.
The researchers focused on epithelial cells for their research as these cells have built-in mechanisms that control cell proliferation and growth. This means that they maintain a certain density of cells in a given area for ideal homeostasis and tissue morphogenesis. Prior research suggests that a possible trigger of the abnormal growth of cells typical of cancer could be the result of a defect in such a mechanism, potentially brought about by genetic changes and mutations over time. The researchers started with a sample of 40 million epithelial cells from mice.
The researchers developed a fluorescence-activated cell sorting assay; this marked the stages of the cell in different flurophores. They combined this assay with a genome screening using CRISPR. This screening searched for cells that replicated normally at low density but continued to do so at a high cell density. This screening highlighted the potential importance of a gene called TRAF3. This gene, which had not been linked to cancer in any past studies, is typically associated with immunity activation.
In cells that lost TRAF3, which also regulates NF-κB signaling, this signaling becomes uncontrolled and causes an innate immune response that causes uncontrolled cell division that does not account for normal cell growth density mechanisms present in epithelial cells. In some epithelial cancers, mutations impacting TRAF3 have been found, and low expression of it has been linked to worse outcomes overall.
Why Does it Matter?
In recent years, research into understanding the growth mechanisms of cancer has become an important aspect of cancer research. Several other discoveries have been made in this area. Last September, for example, a Johns Hopkins team completed a study in which it was able to successfully halt the replication of breast cancer cells. This was achieved by inhibiting the PLK4 protein, which interfered with a structure inside cells that is critical for the cell division process.
Another study from 2018 determined that an enzyme called DHODH could cause cells to stop dividing. Another study used CRISPR to delete the Tudor-SN protein, which slowed down cell division. Ultimately, these discoveries could help lead to new approaches and treatments that have the potential to halt the abnormal cell growth behind every cancer; however, given the great diversity of cancer types, it is likely that different forms may harness different mechanisms in order to grow. Only further research into this area of cancer can reveal these mechanisms in the ways in which they could be stopped.