The long game

Discovery reveals a key to melanoma’s immortality.
Photography by
Angela Hinchie/Alder lab

When Pattra Chun-on first reached out to Jonathan Alder hoping to join his lab at the School of Medicine, Alder was hesitant.

Chun-on, an internist with a background in cancer biology, had come to the University of Pittsburgh for a PhD and wanted to study the extra-long telomeres found in cancer. Telomeres are the caps at the end of chromosomes that protect DNA from degrading. In healthy cells, they become shorter with each cycle of replication until the cell can no longer divide. Cancer cells, meanwhile, have telomeres that maintain their length, allowing the cancer to continue replicating and keeping them effectively immortal.

Though she was an excellent candidate, Alder told the physician that his lab focused on short telomeres, associated with premature death and aging, not the long ones she was interested in. But Chun-on insisted. “This went on until I realized that Pattra would never take ‘no’ for an answer,” says Alder, a PhD assistant professor of medicine.

Her persistence paid off. Chun-on, Alder and their collaborators found a combination of mutations that promote extra-long telomere growth in melanoma, a discovery that could change the way oncologists understand and treat it.

Published in the journal Science in November, their findings identified two genetic alterations that work together to stimulate telomerase, the enzyme that keeps telomeres from shortening. Until now, no one had ever seen them work together to help make melanoma immortal.

“We did something that was, in essence, obvious based on previous basic research and connected back to something that is happening in patients,” Alder says.

For years, scientists have seen strikingly long telomeres in melanoma tumors, especially compared to other cancers. About 75% of melanoma tumors contain mutations in the TERT gene that activate telomerase and allow cells to continue growing. Yet, when scientists mutated TERT in cells in culture, they couldn’t produce extra-long telomeres. It turns out that TERT promoter mutations were just half of the story.  

The road to discovering the other half began when Chun-on heard a talk from Patty Opresko, a PhD professor of environmental and occupational health in Pitt’s School of Public Health who studies DNA damage and repair at telomeres.

“She gave a talk that was so impressive to me,” Chun-on says, “and I just decided, ‘Oh, I will focus on the telomere angle with cancer.’”

As it turned out, Alder had tried studying long telomeres before. Years earlier at Johns Hopkins University, where Alder earned his PhD, he had bandied about an ambitious idea with Carol W. Greider, the Nobel winner who discovered telomerase: What if they could classify all cancers by how they maintain their telomeres? The idea fizzled out in 2015; four years later, Chun-on was taking it up again.

Alder’s team had previously discovered a region in a telomere-binding protein called TPP1 that was often mutated in melanoma tumors. Chun-on found that mutations in TPP1 were strikingly similar to those of TERT. “Biochemists more than a decade before us showed that TPP1 increases the activity of telomerase in a test tube, but we never knew that this actually happened clinically,” Alder says.

When Chun-on—a PhD candidate in Environmental and Occupational Health in the School of Public Health—added mutated TERT and TPP1 back to cells, the two proteins together created the distinctively long telomeres seen in melanoma tumors. TPP1 was the missing factor scientists had been searching for, and it was hiding in plain sight.

By identifying a telomere maintenance system that is unique to cancer, scientists now have another target for the development of new chemotherapeutics.

Alder’s team collaborated on the National Institutes of Health–funded study with researchers at the UPMC Hillman Cancer Center. John Kirkwood, the Sandra and Thomas Usher Professor and Distinguished Service Professor of Medicine, Dermatology and Translational Science at Pitt and coleader of the UPMC Melanoma Program, provided many of the cell lines the team used.

“We were in the right place, and many things lined up,” Alder says. “But so much of this was driven by Pattra’s absolutely unbreakable determination.”