Scientists from the Paul Scherrer Institute (PSI) have recently teamed up with pharma company F. Hoffmann-La Roche AG to identify the structure of a receptor that is essential in the migration of cancer cells. Using the Swiss Light Source to do so, these researchers have brought oncologists one step closer to combatting the metastasis of malignancies. Their work was recently published in the journal Cell.
Once cancer cells make biological transitions that give them mobility throughout the body, metastases, or secondary tumors, begin forming in other organs. Metastatic cancer is extremely dangerous, with roughly 90% of all cancer fatalities resulting from these secondary tumors. Cancer cells that have mobilized spread throughout the body via the lymphatic system, which functions in part to transport white blood cells during immune reactions.
Targeting the CCR7 Receptor
The researchers focused their work on a specific membrane protein, chemokine receptor 7 (CCR7), which places an important role in the migration of white blood cells. They were able to identify the structure of CCR7 for the first time, creating a foundation for the development of anti-metastasis drugs.
CCR7 is a receptor that mediates cell movement within the body. Once the proper protein binds to this receptor, a cascade of reactions cause the cell to move towards the area with high signaling protein concentration. This process is important in directing white blood cells in the lymph system, helping these cells localize to the lymph nodes and sites of infection. The CCR7 system is also leveraged by cancer cells, which use protein signals to migrate from the tumor into the lymphatic system via these receptors.
Being that secondary tumors are correlated with such a high risk of mortality, researchers have long been developing ways to suppress metastasis. Targeting the CCR7 protein that plays such a pivotal role in cell mobility, these PSI researchers have utilized X-ray crystallography better understand the receptor’s structure. Identifying this protein’s structure served as the basis for their research of potential therapeutic agents.
“The right molecule can prevent the signaling protein from coupling to the receptor and causing a reaction in the cell”, said study author Steffen Brünle, a postdoctoral researcher who took part in the work.
Project co-leader Jörg Standfuss described the difficulty the research team had in deciphering the CCR7 structure, saying that “the difficult thing about it was producing them, in the first place, in such a way that we could examine them with X-ray crystallography.” Standfuss is also involved with the Time-Resolved Crystallography research group at PSI. To facilitate the research process, Roche created a novel protein modification technology, known as crystallization chaperones.
Creating a Metastasis Inhibitor
Given this extensive knowledge of the CCR7 structure, the team was able to identify a molecule that blocks the receptor and prevents the signaling processes that lead to cancer cell mobility.
“Our experiments show that the artificial molecule, inside the cell, binds to the receptor. This keeps the chain reaction that leads to cell migration from getting started”, explained Brünle.
Roche scientists used a computer simulation to search through millions of molecules in a database to identify five potential candidates for blocking CCR7. In addition, one of the agents identified by these researchers is already being tested in clinical trials as a potential metastasis combatant. This compound was previously thought to bind and inhibit a different receptor, however, this new study shows it plays a role in CCR7 inhibition.
Suppressing the chain reaction in the cell: #PSICH researchers identify a molecule that blocks a receptor that triggers cell migration and the formation of certain cancerous metastases. https://t.co/jGABO3j5UT
— PaulScherrerInstitut (@psich_en) August 22, 2019