Scientists at the University of Pittsburgh School of Medicine have identified a critical missing piece in the long-standing mystery of how melanoma tumors avoid death and continue to grow.
This week I am writing: scienceDr. Jonathan Alder and colleagues describe a combination of genetic changes that can dramatically extend the lifespan of melanoma cells while promoting rapid tumor growth. The discovery could reshape the way researchers understand melanoma and could suggest new treatment strategies.
“We’ve done something essentially obvious based on previous basic research and tied it to what’s going on inside the patient’s body,” said Alder, an assistant professor in the Division of Pulmonary, Allergy, and Critical Care Medicine at Pitt School of Medicine.
Telomeres help control cell lifespan
Telomeres are protective caps located at the ends of chromosomes that prevent DNA from being broken down. Each time a healthy cell divides, its telomeres become shorter. Eventually, the cells shrink until they can no longer divide.
Keeping your telomeres at the proper length is very important for your health. Telomeres that are too short can lead to disorders associated with premature aging and early death. On the other hand, abnormally long telomeres are often associated with cancer.
Scientists have long known that melanoma tumors contain extremely long telomeres, especially compared to many other types of cancer.
“There is a special link between melanoma and telomere maintenance,” Professor Alder says. “For melanocytes to turn into cancer, one of the biggest hurdles is to immortalize themselves. If they can do that, they’re well on their way to cancer.”
The missing genetic link behind melanoma
The enzyme telomerase lengthens telomeres and helps protect chromosomes and prevent cell death. In most healthy cells, telomerase remains inactive. However, many cancers activate this enzyme through mutations in the telomerase gene, known as TERT, allowing cancer cells to continue dividing.
Melanoma is particularly dependent on this strategy. Approximately 75% of melanoma tumors have TERT mutations that increase telomerase production and activity.
However, there was a mystery. Even after the researchers introduced the TERT mutation into melanocytes, they were unable to reproduce the abnormally long telomeres seen in melanoma tumors. This suggested that another important element was missing.
Dr. Patra Chung-ong, an internal medicine physician pursuing a Ph.D. Alder’s lab set out to uncover that missing link. She used her background in cancer biology and growing interest in telomeres to investigate why TERT mutations alone are not enough.
“What’s interesting about this story is when Patra joined my lab,” Alder said. “She contacted me and said she was interested in cancer research. I told her I was studying short telomeres, not long telomeres. This went on until I realized that Patra would never take ‘no’ for an answer.”
TPP1 completes the puzzle
Previous research from Dr. Alder’s lab identified frequent mutations in a telomere-binding protein called TPP1 while analyzing cancer mutation databases.
Chun-on found that these TPP1 mutations are very similar to TERT mutations. They occurred in the newly annotated promoter region of TPP1 and promoted protein production. The discovery immediately caught Alder’s attention because scientists had already shown that TPP1 increases telomerase activity.
“More than a decade ago, our biochemists showed that TPP1 increases telomerase activity in vitro, but we had no idea that this was actually happening clinically,” he said.
Chun-eon is also enrolled in a doctoral course. program at the Pitt School of Public Health’s Department of Environmental and Occupational Health, where he introduced mutant forms of both TERT and TPP1 into cells. The two proteins worked together to generate the extremely long telomeres that are a hallmark of melanoma tumors.
The results revealed that TPP1 is a long-sought, hidden, missing factor.
New targets for future melanoma treatment
The findings provide a new explanation for how melanoma develops and survives. They also identified a cancer-specific telomere maintenance system that could be a promising target for future treatments.
Additional authors of this study are Angela M. Hinchie, Agustin A. Gil Silva, Ph.D., Elizabeth Rush, Cindy Sander, Brittani KN Seynnaeve, MD, MS, John M. Kirkwood, MD, all of Pitt, UPMC, or both. Dr. Holly C. Beal and Dr. Olena M. Vaske, both of the University of California, Santa Cruz; Carla J. Connelly of Johns Hopkins University. Dr. Carol W. Grider of the University of California, Santa Cruz and Johns Hopkins University;
This research was supported by National Institutes of Health grants R35CA209974 and R01HL135062.
