A surprising discovery could lead to improved treatments for a wide variety of cancers. It has been challenging to identify the causes of many cancers, as they often seem to have multiple origins. However, fibrolamellar carcinoma (FLC) is a cancer that researchers believed they had identified the cause of.
FLC is a rare and currently untreatable disease that affects the livers of children, adolescents, and young adults. It is caused by a small deletion in chromosome 19 that leads to the fusion of two genes. This discovery was made in 2014 in the laboratory of Sanford M. Simon at Rockefeller University. Simon’s teenage daughter was diagnosed with FLC, which motivated him to research the disease further.The daughter, Elana, not only had liver disease, but she was also a key member of the team that discovered the fusion. One of the genes involved is DNAJB1, which produces heat-shock proteins that help maintain cell balance. The other gene is PRKACA, which produces the catalytic subunit of protein kinase A (PKA), a crucial component in cellular metabolic function. Changes in kinases, which affect many other molecules, have been linked to the development of various cancers. For the past ten years, it was believed that this fusion caused a drastic alteration in PKA, leading to cellular chaos. However, researchers in Sim now believe that this is not the case.The research team at Simon’s lab has made a surprising discovery: the fusion protein acts just like a normal kinase. However, cells with an additional catalytic subunit produce excessive amounts of the kinase, which is the real cause of the problem.
“The actual cause of cancer is the overexpression of a protein called PKA,” explains Mahsa Shirani, the first author and a postdoctoral associate in the Laboratory of Cellular Biophysics, led by Simon. “These findings could potentially reveal the pathways of various cancers and provide new treatment options.”
The results of the study were published in Cancer Research.
A lack of inhibition
Shirani has been focused on gaining a deeper understanding of the mechanics of the fused gene since her time as a Ph.D. student and teaching assistant in the lab of biochemist Barbara Lyons at New Mexico State University. Lyons’ research into FLC was motivated by her own son’s diagnosis with the disease. Just like Elana Simon and many other patients, Lyons’ son, Jackson Clark, took a break from his life to study the disease in Simon’s lab. His first article from the lab was published last year. Unfortunately, Clark passed away from FLC.
For the current study, Shirani examined tumor tissue.Using mass spectrometry, biochemistry, and immunofluorescence, the researcher analyzed samples from FLC patients to measure the protein levels in their tumor tissue, comparing them to normal liver tissue. Upon further investigation, she discovered a molecular imbalance in the tumor cells, with an overabundance of catalytic proteins surpassing the inhibitory ones. This imbalance resulted in increased PKA activity and unrestricted movement of PKA within the cell, causing disruption in areas it typically cannot reach, such as the nucleus.Shirani’s findings suggest that the crucial factor is the active catalytic subunit’s ability to override its inhibitory components, rather than any structural changes in the kinase itself.
When testing this hypothesis, the researchers discovered that they could induce the disease in human liver cells by simply increasing the normal kinase levels. Furthermore, they observed that some patients had a different gene fused to the front end of the PRKACA kinase, indicating that the root cause of the disease could not solely be attributed to the additional kinase piece.
“Our study demonstrates that the fused component to the PRKACA does not have a significant impact on the disease.”gene. It might be DNAJB1 or ATP1B1, or it might not be any specific gene at all — just PRKACA with high protein expression,” she states. “Regardless of the gene involved, the result is the same cancer phenotype.”
The researchers confirmed their findings using a specialized tool available to them. For the past ten years, the Simon Lab has operated the Fibrolamellar Tissue Repository. When the researchers reviewed their samples, they found four patients who appeared to have fibrolamellar but did not have a fusion to PRKACA. Instead, the only change they identified was a loss of the inhibitory protein, providing further evidence.The study found that the ratio of catalytic subunit to regulatory components played a crucial role in the development of the disease.
Potential Treatment Options
These findings have the potential to lead to the development of the first therapeutic treatments for FLC, beyond the current surgical removal of tumors, according to Shirani. (Current treatments for common liver cancer are ineffective for FLC, as it has a different molecular profile.)
One potential approach is to identify binding sites on the DNAJB1 protein that could be targeted by a drug inhibitor. Another option is to reduce the expression of PKA. The research team is currently investigating these possibilities.< p>According to Shirani, the latter approach has the potential to go beyond FLC because dysregulation of PKA is linked to many other diseases. For instance, the adrenal tumor that causes Cushing Syndrome is the result of a mutation in the same catalytic subunit, PRKACA, as discovered by Rockefeller President Richard P. Lifton in 2014. Just like for a potential FLC treatment, the key would be to disrupt signaling processes downstream of PKA’s production before excessive protein production disrupts the cell.
Shirani also suggests that measuring protein levels produced by mutated genes may offer insight into both possibilities.Investigating rare diseases can be an important first step in understanding various cancers. Finding increased levels or changes in the location of proteins could potentially be the cause of these diseases. Dr. Simon emphasizes the significance of studying rare diseases, even though they affect a small number of people. He believes that investigating these diseases can provide valuable insights into the pathogenesis of diseases in general. Rare diseases are often well-defined and understood, which can lead to rapid progress in research. Additionally, the results obtained from studying rare diseases can be applied to more common diseases. For example, the concept of ‘tumor supp
According to researcher, studying the rare childhood cancer retinoblastoma is a significant challenge.
He also believes that as we better understand diseases, we realize that many previously thought to be one disease are actually multiple rare diseases with some common traits or mechanisms,” he adds.
