How Cells Hold Together Could Inform New Disease Treatments
The human body is composed of trillions of cells that must stick together to keep tissues intact. Yet, these same cells also know when to adjust their stickiness to allow wounds to heal. A team of biomedical engineers at the University of California, Davis, will investigate how cells manage this balance, laying the groundwork for potential treatments for cancer and heart diseases.
The research is made possible by more than $3 million Maximizing Investigators' Research Award, or MIRA, from the National Institutes of Health. MIRA supports research with outstanding potential to improve understanding of biological processes and advance disease diagnosis, treatment and prevention.
Sanjeevi Sivasankar, professor and chair of biomedical engineering, leads the project. It builds upon his lab’s extensive research on cadherins, the class of proteins that help cells adhere to one another.
“My group is interested in understanding how cells stick together, how they are able to tune their adhesion and how they withstand mechanical forces,” Sivasankar said. “This is so we can eventually develop tools that prod the cell to do its natural thing and block disease mechanisms from taking hold.”
The Cellular Connections
The project focuses on two types of connections between cells: adherens junctions, found throughout the body’s soft tissues, such as skin, and desmosomes, which are located in tissues that experience a lot of force, such as the heart.
These connections are extraordinarily complex, featuring thousands of cadherin proteins spanning the cell membrane. Sivasankar’s team will study how individual proteins influence the ability of adherens junctions and desmosomes to be strong and adaptable.
Mapping the Sticking Points
The team will use proximity labeling technologies to identify the proteins essential for cellular connections. Sivasankar’s team previously developed a proximity labeling tool capable of following proteins that bind cadherins, including a light-activated technique to illuminate how proteins interact with one another.
Sivasankar plans to develop a new imaging tool capable of activating when two cadherins bond together or when cadherins experience mechanical force. This innovation will allow his team to map, for the first time, the mechanisms by which cellular connections recruit the appropriate proteins to form adherens junctions and desmosomes. It will also enable them to track how these connections change over time or when exposed to mechanical stress.
Unlocking Desmosomes
Desmosomes are extremely strong and tough to separate into their constituent pieces, making the connections challenging to study.
Sivasankar’s team, however, discovered that applying mechanical forces to these connections causes a key protein, desmoplakin, to open up.
In their typical state, think of these connections like a closed fist. But when force is applied, like a squeeze on the wrist, the tissue connections unfurl.
The researchers suspect that when the desmoplakin is in an open state, it attracts additional, unknown proteins that strengthen the desmosome.
Using the team’s proximity labeling tools, the researchers will investigate which proteins are recruited by the desmoplakin and how these different proteins positively or negatively influence the structure of tissues, such as those in the heart.
Sending a Strong Signal
Understanding how cells control adhesion could allow researchers to engineer new medical interventions.
For example, Sivasankar’s team will develop antibodies, which are a type of protein, to probe whether or not they are capable of stabilizing or eliminating specific connective structures.
In some cancers, cells switch between distinct types of cadherins. With these antibodies, the cell could be encouraged to remove the wrong cadherins while maintaining the right ones.
By identifying how protein structures and interactions inform tissue development, Sivasankar’s team aims to establish the knowledge needed before new ways to prevent or treat diseases like cancer can be developed.
“It’s a question of understanding how the biology actually works first and then being able to engineer this biology,” Sivasankar said.
