A Brock-led research team has discovered a mechanism that provides new insights into stopping the spread of various cancers by controlling a stage of cell signalling, a process through which cells communicate with one another.
Associate Professor of Biological Sciences Aleksandar Necakov and his team focused on the Notch receptor, a protein found on the surface of many human cells.
Notch receptors receive information from outside the cell through direct physical contact with neighbouring cells and pass this information into the cell to control gene expression.
"The Notch receptor plays an important role in many human cancers," says Necakov. "Our discovery of a novel mechanism that controls Notch signalling provides new opportunities to regulate, and thereby inhibit uncontrolled cell proliferation."
For example, Notch signalling is active at very high levels in human t-cell lymphoblastic leukemia, Necakov says, and turning off the Notch pathway in this case, and in other types of cancer, "shuts off the ability of cells to multiply."
To better understand the Notch signalling process, then-PhD student Gregory Foran (BSc '18, PhD '24) used a technique known as optogenetics to engineer a specialized Notch receptor that uses light to activate Notch signalling in human cells.
When Foran shone blue light onto cells with the receptors he had engineered, the Notch receptor was freed from the plasma membrane and moved into the cell nucleus, where it resulted in changes in gene expression.
Through this process, the team was able to identify a key driver of cell proliferation called MYC proto-oncogene and also that this new Notch receptor provides precise control over the levels of target gene expression.
"The tool we generated allows us to use light to follow the real-time dynamics of signalling to get at the underlying mechanisms that govern this important pathway," says Foran, who is now a Research Associate at the Baylor College of Medicine in Texas. "I feel proud that I was able to lead research that's led to some key discoveries and understanding as to how cellular signalling works."
Foran says this discovery could potentially lead to cancer therapies down the road following more research.
The team also included Biological Sciences PhD students Marvel Megaly, Anel Turgambayeva and Ryan Hallam, who collaborated with researchers at the Moffitt Cancer Center in Florida.
The team's findings are featured in a research article titled: "Notch1 Phase Separation Coupled Percolation facilitates target gene expression and enhancer looping," published last year in the journal Scientific Reports.
Necakov says the next step in the research is to study the role of Notch self-assembly in the context of human breast cancer, with a focus on the integration of other cell signalling pathways through the self-assembly mechanism they have discovered.
