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MetroHealth and Case Western Reserve University (CWRU) cancer researchers have solved a mystery surrounding a receptor protein that can suppress cancer or make it grow and spread. Their findings, detailing how and why the EphA2 receptor plays the roles of both cancer hero and villain, will be published in the journal Science November 16.

The team of researchers was led by Bingcheng Wang, PhD, Director of the MetroHealth Division of Cancer Biology and MetroHealth Research Institute Director of Basic Sciences.

Discoveries like this make it possible to treat cancer, said Dr. Wang, who also is the John A. and Josephine B. Wootton Endowed Chair of Research and professor at the Case Western Reserve School of Medicine and a member of the Case Comprehensive Cancer Center. As a cancer researcher, there is no greater accomplishment. Being asked to share this work with the scientific community through the prestigious journal Science is an honor. But the greatest reward is to know that we are making strides that will have a real impact on our own patients and others throughout world.

Dr. Wang, who has been studying the EphA2 receptor for 25 years, is recognized as a pioneer in the field. His lab has made several key discoveries around the receptor, which is overexpressed in solid tumors like prostate, breast, colon and lung cancers as well as the aggressive brain tumor glioblastoma.

In two landmark studies published in Nature Cell Biology in 2000 and 2001, Dr. Wangs lab was the first to make the groundbreaking discoveries that the EphA2 can suppress malignant behaviors of cancer cells. In 2009, his team reported in Cancer Cell that the same receptor also can have the opposite function after being modified by tumor-promoting proteins. The modified EphA2 causes cancer cells to proliferate, maintain stem cell properties and metastasize to other parts of the body.

Now, after years of investigation, the researchers have figured out how EphA2 plays these dual, opposing roles in cancer. Using a cutting-edge spectroscopic platform (PIE-FCCS) that allows molecular analysis on live cells, they saw that EphA2 is automatically assembled into small clusters on live cells through two different types of interactions among adjacent EphA2 molecules that glue them together. One interaction contributes to the hero role and the other triggers the villain side of the molecule.

The first author of the paper is Dr. Xiaojun (Roger) Shi, a postdoctoral scholar at the CWRU School of Medicine and a current trainee with the Cancer Biology Training Program of the National Cancer Institute. Roger made the discovery by combining his expertise in molecular imaging during doctoral thesis work and mastery of experimental cancer biology gained in the Wang lab.

As the lead contact author, Dr. Wang shares the findings in the Science article Time-Resolved Live Cell Spectroscopy Reveals EphA2 Multimeric Assembly. A large multidisciplinary team contributed to the work. Dimitar B. Nikolov, of Memorial Sloan Kettering Cancer Center, and Adam W. Smith, of Texas Tech University, are co-corresponding authors of the paper. Khalid Sossey-Alaoui, of MetroHealth and CWRU; Matthias Buck, of CWRU; Ben Brown and Jens Meiler, of Vanderbilt University; and Dolores Hambardzumyan, of Icahn School of Medicine at Mount Sinai, are among the co-authors who contributed to the work. The paper will be published online by the journal Science on Thursday, November 16.

As the inaugural Director of the Division of Cancer Biology in the Department of Medicine, Dr. Wang has played a significant role in MetroHealths strategic vision for research, successfully recruiting several nationally recognized cancer researchers. In 2021, he led the formation of a new Cancer Research Team, funded through millions of dollars in support and grants, to focus on ending the racial, ethnic, social and economic inequities that impact cancer diagnosis and treatment.

We know that many types of cancer disproportionately affect people of color, said MetroHealth President & CEO Airica Steed, Ed.D, RN, MBA, FACHE. This is why we are hyperfocused on eradicating health disparities and will continue to support the cutting-edge research that leads to these discoveries, so eventually all patients who face a diagnosis of cancer can hope for a long life, regardless of their cultural background, where they live or how much money they make.

John Chae, MD, MetroHealth Senior Vice President, Chief Academic Officer, said Dr. Wangs discoveries and other pivotal research being done at MetroHealth are reinforcing the Systems reputation as a world-class research institution.

This is the sort of foundational research that life-saving therapies are built upon, said Dr. Chae, who also is Senior Associate Dean for Medical Affairs at the CWRU School of Medicine. We are fortunate to have internationally respected researchers like Dr. Wang and the incredible team he has assembled. We will go on supporting this research and proving that some of the very best science in the world is being done in Cleveland at The MetroHealth System.

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