Keeping Cell Junctions Tight to Keep Cancer Out
Ian C. Summerhayes, PhD, is executive director of research and director of the Cell and Molecular Biology Laboratory at Lahey Clinic. Summerhayes currently focuses on three interconnecting areas of research: adhesion proteins (specifically the cadherins) involved in tumor progression, cadherin signaling events, and small molecules that interfere with tumor metastasis. He is also developing a proteomics program at Lahey to further these and other research interests.
After receiving his PhD in tumor/molecular and cell biology from the Imperial Cancer Research Fund in London, Summerhayes did postdoctoral training at the Dana-Farber Cancer Institute. (In 2002 the Imperial Cancer Research Fund amalgamated with the Cancer Research Campaign to form Cancer Research UK.) He was a staff scientist at the Institute of Cancer Research in London. His academic appointments at Harvard Medical School have included instructor in pathology, assistant professor of surgery, and associate professor of surgery.
As executive director of research at Lahey Clinic, a major teaching affiliate of Tufts University School of Medicine, Summerhayes trains surgical residents during their year of laboratory research. “They’re a great link for us to try to understand what the clinical problems are and to keep us focused,” says Summerhayes. “A year is not a long time, but it’s certain to introduce them to technologies and ideas that will feature in their practices later on down the road. From this training, they’ll have an understanding of the goals of molecular medicine and we hope they will remain active in research throughout their careers.”
Adhesion proteins bind cells tightly together, in part preventing tumors from invading adjoining tissues. Changes in adhesion proteins that disrupt cell–cell contacts and promote migration enable tumor cells to invade. Summerhayes and his research group have identified a number of different cadherin adhesion proteins that are subject to a process known as cadherin switching, through which one cadherin gets switched off and another gets switched on. This switching can enable a tumor to become invasive. “We’re also interested in the signaling events that are associated with these changes so we can try to identify targets that may be useful to specifically eliminate cells that have acquired invasive potential,” says Summerhayes. He and his colleagues are looking at many of the small molecules now being generated by biotech companies for their ability to interfere with changes associated with invasion.
Summerhayes believes the proteomics program he is developing at Lahey will be a great asset to the understanding of proteins involved in tumor progression. Proteomics is broadly defined as the study of proteins and their functions. “Within the clinical setting, you could use it to get a proteomic fingerprint from different tissues that will define different stages of tumor progression,” he explains. “We’re interested in the protein because that is the effector molecule.” Although gene expression arrays can tell you which genes are turned on and which are turned off, this technique cannot tell you the quantity or effective activity of the protein. Also, once a protein is made it can be altered in ways that change its activity, such as through phosphorylation. Proteomics can provide a clearer idea of protein status.
One proteomics technique Summerhayes uses involves reverse phase microarrays in which lysate from a tissue is spotted onto a slide and incubated with an antibody that targets a protein of interest. “We can array hundreds of lysates from different tumors on a single slide and then probe with antibodies that define different events implicated in disease progression,” says Summerhayes. Such high-throughput techniques generate immense quantities of data that require advanced statistical analysis, a methodology Summerhayes hopes to gain through a collaboration with the statistics team at Tufts. Because proteins present significant challenges in arraying, Summerhayes is working with a biotech company that has made a new microarrayer that overcomes many of the problems (particularly those related to precise delivery of protein samples) encountered with existing devices.
“Ten years down the road, this is where I’d perhaps envisage part of clinical care,” says Summerhayes. “You take a biopsy and make the lysate, identifying a proteomic signature that will provide diagnostic, prognostic, and therapeutic response information that will guide the clinical management of the patient.” Summerhayes says that proteomic profiling should be run in parallel with genomic (DNA) profiling because each provides different information that aids in the identification and treatment of cancers. “The expression that goes with the DNA profiling gives you one set of information, with its limitations, and the proteomics will give you another set of information, with its limitations. Then we also do tissue microarrays and they give you another set of information—the localization of protein that you don’t get from the other techniques. So all of these high-throughput techniques run in parallel give you massive amounts of very useful information, complementary to each other. The bottleneck right now is in handling all of that data.”
Summerhayes works closely with Kimberly Rieger-Christ, PhD, of Lahey Clinic and collaborates on breast cancer research with Amy Yee, PhD, of the Sackler School of Graduate Biomedical Sciences. He is also working on non-invasive screening for bladder cancer and on a tissue engineering project with Lahey’s David Bryan, MD, that involves using bioresorbable conduits in nerve regeneration.
For more information, please contact Dr. Summerhayes at Ian.C.Summerhayes@lahey.org.