Image displays focal adhesions in red, microtubules in green, DNA in blue, and actin in gray

“Watch out, shark!” Your response to someone yelling this while you sit at your office desk would be very different than if you had been swimming in the ocean. Just like we respond to cues based on our environment, so do cells, and cancer cells are particularly good at adjusting to environmental changes. One of these environmental changes is the stiffness of the material that surrounds the cells. This material, the extracellular matrix, is a scaffold of fibrous proteins that is both sturdy enough to provide architectural support and dynamic enough to remodel itself. As tumors grow, the surrounding extracellular matrix remodels, thickens, and stiffens. Cancer cells respond to these environmental changes by growing more rapidly, becoming more mobile and invasive, and increasing defenses to avoid cell death. However, little is known about how cancer cells connect environmental changes to cellular communication in order to thrive in changing environments. 

Now, new work from UVM Cancer Center member, Alan Howe, PhD, highlights a newly identified pathway that connects the properties of the extracellular matrix to signals that control cell mobility/motility. The study, published in the Proceedings of the National Academy of Sciences, provides a better understanding into how cells incorporate changes in physical cues into cellular communication.

Focal adhesions are specialized structures that form a link between the external environment and internal machinery of the cell. Previous work from the Howe lab found that, unexpectedly, the signaling protein PKA is a component of focal adhesions. This new body of work shows that PKA interacts with the protein talin to integrate external cues into internal cellular communication. Talin is a critical component of the mechanical interactions between cells and their environment. This new work highlights how, as cells pull against the extracellular matrix, the tension exerted results in the stretching of talin and subsequent interaction with PKA. This novel integration between the external environment and talin serves as a signaling complex that couples the sensing of external cues with cellular communication.

Future work in the lab will focus on determining how cells control the interaction between PKA and talin, pinpointing which additional proteins PKA interacts with as a result of its affiliation with talin, and determining how changing these interactions affects cell motility and invasion.

This work was made possible through the effort and dedication of Mingu Kang, PhD, a graduate student in the Howe lab. The identification of PKA as a component of focal adhesions was further supported by graduate students Hannah Naughton, Amanda Senatore, and Madeline McTigue. The work was made possible by funding from the National Institutes of Health and a UVM Cancer Center pilot grant.

If you would like to learn more, view the published manuscript here.