Outside-in signaling shows a route into cancer cells

(Press-News.org) A new study shows how an anticancer drug triggers an “outside in” signal that gets it sucked into a cancer cell. The work, published Jan. 29 in Nature Communications, reveals a new signaling mechanism that could be exploited for delivering other drugs. 

Many malignant cancers overexpress a protein called P-cadherin, which is embedded in the cell membrane. Because cancer cells have a lot of P-cadherin sticking out of their surface, the protein has been targeted for drug development. 

Monoclonal antibodies against P-cadherin can carry a drug payload to the cancer cells. It has not been clear, though, exactly how the antibodies attach to P-cadherin or how they get inside the cancer cell once attached. 

Bin Xie and Shipeng Xu, graduate students in biophysics and biomedical engineering at the University of California, Davis, with Professor Sanjeevi Sivasankar, carried out a series of experiments to study binding of antibody CQY684 to P-cadherin in detail. 

P-cadherin is embedded in the cell membrane as a dimer, or matched pair, with P-cadherin on the surface of an adjacent cell. This dimer can exist in two conformations: a more open, “strand-swap” dimer and a cross-shaped, X-dimer. 

The researchers found that when the anti-cancer antibody binds to P-cadherin, it locks it into the X-dimer form. The stable X-form then triggers a chemical signal that causes that patch of membrane to be pinched off and sucked into the cell as a tiny bubble. The whole P-cadherin/antibody/drug complex is then sent to a structure called the lysosome to be broken down. 

“Our results establish an outside-in signaling mechanism that provides fundamental insights into how cells regulate adhesion,” the authors wrote. Understanding the binding targets for antibodies against cadherin could help design drugs that exploit this pathway to find and destroy cancer cells.

The work was supported in part by a grant from the National Institutes of Health. 

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