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Using a powerful single-molecule imaging method they developed, a ӳ����ý research team has unveiled a dynamic view of how some cancer-related proteins interact in living cells. The technique relies on highly stable nanoparticle probes that brightly illuminate individual molecules for long periods of time. The researchers used their method to observe, for the first time, individual receptors as they move around the cell membrane, attaching to and then letting go of other receptors to alter signaling within the cell.

Described in , the work demonstrates the method’s potential for investigating other receptors and molecules and for improved drug screening to better understand the effects of therapeutics on living cells.

“With our photostable probes, we can map out the entire lifespan of these molecules in their native environment and see things that have never been observable before,” said study leader Sam Peng, a ӳ����ý core institute member and assistant professor of chemistry at MIT.

Molecular movies

Peng’s method solves a problem with existing contrast agents used in single-molecule tracking such as dyes. Under the laser light that’s used to excite these dyes, they burn out after a few seconds in a phenomenon known as photobleaching, which means that scientists could only use them to take a few snapshots of cell receptors and not follow them over the entirety of the signaling process.

For a longer and richer view, Peng’s lab , known as upconverting nanoparticles, which emit signals that remain stable under laser excitation. The nanoparticles contain rare-earth ions that continue to luminescence for minutes, hours, and potentially years. In addition, by altering the type and doses of the ions, scientists can engineer probes emitting in many different colors, enabling tracking of many targets in a single experiment.

In the current study, the researchers aimed to uncover new biology by focusing on the EGFR family of cell receptors, which have been linked to several kinds of cancer. They collaborated with EGFR experts Matthew Meyerson and Heidi Greulich of the ӳ����ý’s Cancer Program. They knew that EGFR receptors need to pair up, or “dimerize,” in order to initiate signaling within the cell, but they wanted to learn more about the dynamics of these pairings — what the receptors partner with, how long they stay together, and how they find new partners.

For a better and more sustained look at the receptors, the research team customized their upconverting nanoparticles to tag EGFR and related receptors HER2 and HER3, which are linked to cancer, and used them to track the molecules in living human cells.

A new view of protein pairings

In this study, Peng and his team observed that, when activated with a stimulating molecule, EGFR receptors can pair up and stay dimerized for several minutes, something not observable using traditional dyes. Excessive and prolonged dimerization can lead to too much cell growth and cancer.