New method enables more precise labeling of protein-protein interactions in cancer-specific cells

Using a photochemically driven labeling technique, a Cornell University-led research group has devised a strategy for capturing cancer-specific protein-to-protein interactions, which could one day spawn targeted therapies for prostate, small-cell lung, pancreatic and other deadly forms of the disease.

By targeting the molecules that surround and support the hard-to-access c-Myc protein, which is essential for tumor growth, the group led by Ciaran Seath found a way to characterize the protein in a cancer-only context. They found it was regulated in cancer by a signaling protein called SLK, which is prevalent in both healthy and cancerous cells, and at around the same concentration in both, so has been largely ignored by the biomedical community.

Rather than looking at whether protein levels are elevated or not, we're looking at where they are. We've identified something that is really vital for this set of cancers to grow and proliferate, and that kind of opens up this whole field."

Ciaran Seath, Assistant Professor, Department of Chemistry and Chemical Biology

Seath is corresponding author of "Photoproximity Labeling of c-Myc Reveals SLK as a Cancer-specific Co-regulator," which published Aug. 13 in Nature Chemical Biology.

Seath and his lab adapted a nanoscale proximity labeling method, called "µMap" (MicroMap), which enables more precise labeling of protein-protein interactions that occur in cancer-specific cells, including those involving c-Myc, a transcription factor that controls cellular growth and is deregulated – a.k.a. out of control – in nearly half of all cancers.

For this study, the group attached the chemical antennas onto c-Myc proteins in three prostate cell lines, representing healthy prostate, AR-negative prostate cancer and AR-positive prostate cancer. Comparing the three "interactomes" revealed several common partners, but cross-referencing these with the open-access DepMap cancer database highlighted SLK as a protein of interest in AR-negative prostate cancer.

A closer look at SLK in this context revealed that its localization in the cell was completely different – in the nucleus, which allowed it to stabilize c-Myc.

"When you have this transcription factor that has maybe 10, 20 or 30 times its regular protein, it can start to go places it shouldn't and interact with things it shouldn't," Seath said. "Once we identify those kind of novel complexes, we can use them as a handle to treat the disease only, and not impact the healthy cells. Using µMap enabled us to look very precisely at those interactomes, those 'neighborhoods,' in disease."

Their precision labeling technique identifies SLK as a driver of cancer but only in certain contexts. Healthy cells can use this nuclear SLK to regenerate tissue – sunburned skin is an example, Seath said. But cancerous cells co-opt SLK's regenerative ability to drive growth.

Seath said work is ongoing in his lab to develop therapeutic small molecules based on the findings in this work. "Hopefully we keep going and are able to launch companies and develop clinical molecules based on this discovery," he said.

Support for this work came from the National Institutes of Health.