The receptor is called "CXCR4" - the subject of heated debate among experts in recent years due to its mysterious relationship status. Does it appear in singles or pairs on the cell membrane? And what makes the difference? The research team of the Receptor Signaling Lab at the MDC, has now solved the puzzle of its relationship status for the first time. Their findings were recently published in the journal "Proceedings of the National Academy of Sciences" (PNAS).
CXCR4 is an important receptor on immune and cancer cells
"When CXCR4 is found in large numbers on cancer cells, it also ensures that they can migrate, thereby laying the foundation for metastases," says lead author Isbilir. Metastases are known to be difficult to treat; some patients die as a result of these secondary tumors.
CXCR4 is also involved in inflammations. The center of inflammation releases messenger substances from the chemokine class. In lymph nodes, chemokines ensure that immune cells form many CXCR4 receptors on their membrane. With the help of these receptors, immune cells can locate the center of inflammation and migrate to it. The name CXCR, which stands for "chemokine receptor," also refers to this ability. "Such receptors are the most important target structures in pharmaceutical research," emphasizes Professor Martin Lohse, the last author of the study. "Approximately one-third of all drugs address this class of receptors."
Fluorescent pairs and singles
The scientists combined two recent optical microscopy methods: Using single-molecule microscopy, they were then able to determine the relationship status of individual CXCR4 receptors on the surface of living cells. Fluorescence fluctuation spectroscopy also made it possible to measure the relationship status in cells that had a large number of receptors. The special feature here: to do this, the researchers had to develop a method to efficiently mark all receptors. They also had to develop a highly sensitive microscopy strategy with which they could see individual molecules and their oligomerization.
"The exciting thing is that we can now use these fluorescence methods to study living cancer cells. We can find out whether CXCR4 is present in pairs or alone," says Annibale, who is co-head of the Receptor Signaling Lab. "And then we can apply CXCR4 blockers to singles and pairs and test which are more effective against tumors. This will hopefully lead to more specific cancer drugs with fewer side effects."
Pathologists today are also examining the properties of patients' cancer cells in detail. This allows cancer therapies to be designed in the most personalized and effective way possible. Annibale hopes that the approach could be now used for screening the effects of different drugs on the function of this and similar receptors. This could be helpful in devising new therapies for breast, or lung cancer, for example.
Işbilir et al. Advanced fluorescence microscopy reveals disruption of dynamic CXCR4 dimerization by subpocket-specific inverse agonists. PNAS November 17, 2020 117 (46) 29144-29154; https://doi.org/10.1073/pnas.2013319117 [Article]