Cancer Mystery Solved: Scientists Discover How Melanoma Tumors Control Mortality

Red Cancer Cells Concept

Melanoma is a type of skin cancer that develops in the cells (melanocytes) that produce pigment in the skin. It is a more aggressive form of skin cancer and can spread (metastasize) to other parts of the body if not detected and treated early.

A team of scientists from the University of Pittsburgh School of Medicine has found the missing puzzle piece in the mystery of how melanoma tumors control their mortality.

In a paper published in Science, they describe how they identified the specific genetic changes that allow tumors to grow rapidly while also preventing their own death. This discovery could have significant implications for the way melanoma is understood and treated by oncologists.

Jonathan Alder

Jonathan Alder, Ph.D., assistant professor in the Division of Pulmonary, Allergy and Critical Care Medicine at the University of Pittsburgh School of Medicine. Credit: University of Pittsburgh

“We did something that was, in essence, obvious based on previous basic research and connected back to something that is happening in patients,” said Alder, assistant professor in the Division of Pulmonary, Allergy, and Critical Care Medicine at Pitt’s School of Medicine.

Telomeres, protective caps at the end of the chromosome, are required to prevent DNA from degrading. In healthy cells, telomeres become shorter with each cycle of replication until they become so short that the cell can no longer divide. Disruptions in maintenance of the length of the telomeres can lead to severe disease. Short telomere syndromes lead to premature aging and death, but extra-long telomeres are associated with cancer.

For years, scientists have observed strikingly long telomeres in melanoma tumors, especially in comparison with other cancer types.

“There’s some special link between melanoma and telomere maintenance,” said Alder. “For a melanocyte to transform into cancer, one of the biggest hurdles is to immortalize itself. Once it can do that, it’s well on its way to cancer.”

The telomerase protein is responsible for elongating telomeres, protecting them from damage, and preventing cell death. Telomerase is inactive in most cells, but many types of cancers use mutations in the telomerase gene, TERT, that activate this protein and allow cells to continue growing. Melanoma is particularly well-known for doing just this.

About 75% of melanoma tumors contain mutations in the TERT gene that stimulate protein production and increase telomerase activity. Yet, when scientists mutated TERT in melanocytes, they weren’t able to produce the same long telomeres seen in their patient’s tumors. It turned out that TERT promoter mutations were just half of the story.

With a background in cancer biology and a new interest in telomeres, Pattra Chun-on, M.D., an internist earning her Ph.D. in Alder’s lab, was determined to find the missing link between melanoma, TERT promoter mutations, and long telomeres.

Pattra Chun On

Pattra Chun-On, M.D., a Ph.D. student at the University of Pittsburgh School of Public Health Department of Environmental and Occupational Health. Credit: Pattra Chun-On

“The fun part of this story is when Pattra joined my lab,” Alder said. “She contacted me and told me that she was interested in studying cancer. I told her that I study short telomeres and not long telomeres. This went on until I realized that Pattra would never take ‘no’ for an answer.”

While combing through cancer mutation databases, Alder’s lab team had previously discovered a region in a telomere-binding protein called TPP1, which was often mutated in melanoma tumors.

Chun-on’s determination in the lab shone when she found that the mutations in TPP1 were strikingly similar to those of TERT; they were located in the newly annotated promoter region of TPP1 and stimulated the production of the protein. This was exciting to Alder because TPP1 has long been known to stimulate telomerase activity.

“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,” he said.

When Chun-on – who is also part of a Ph.D. program in the Department of Environmental and Occupational Health at Pitt’s School of Public Health – added mutated TERT and TPP1 back to cells, the two proteins synergized to create 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 all along.

This discovery has changed the way scientists understand the onset of melanoma, but it also has the potential to improve treatment. By identifying a telomere maintenance system that is unique to cancer, scientists have a new target for treatments.

Reference: “TPP1 promoter mutations cooperate with TERT promoter mutations to lengthen telomeres in melanoma” by Pattra Chun-on, Angela M. Hinchie, Holly C. Beale, Agustin A Gil Silva, Elizabeth Rush, Cindy Sander, Carla J. Connelly, Brittani K.N. Seynnaeve, John M. Kirkwood, Olena M. Vaske, Carol W. Greider and Jonathan K. Alder, 10 November 2022, Science.
DOI: 10.1126/science.abq0607

The study was funded by the National Institutes of Health.

12 Comments on "Cancer Mystery Solved: Scientists Discover How Melanoma Tumors Control Mortality"

  1. No…this is not correct about Teleomeres. Nor how cancer cells become immortal.

  2. Thank you for the insight Dr. Craig. Please enlighten us further…

  3. Yes! Please Dr Craig? The article seems accurate- but I’m open to other researchers opinions. I’m just a caregiver for a cancer patient.

  4. Interesting.

    Well done Pattra. Never thought your childhood fairy tales would help you solve one of the world’s challenging problems, did you?

    Goldilocks and the the three Bears.

    The Telomere was not too long and not too short. Just Right.

  5. Please find a cure for metastatic breast cancer

    • David B. Karpf, MD | January 10, 2023 at 6:19 pm | Reply

      This is fundamentally important work. As VP of clinical development at Geron from 2001 to 2004, I gained some level of experertise in hTERT and both cancer (using TERT inhibitors) and senecence prevention (using TERT promoters). The fact that Carol Greider is an author on this paper provides an additional guarantee of the scientific validity of this paper.

  6. This cure is for how many year to waith to use for a 18 year girl with cancer who now is spreading every where in her body,they stop with the treatment now is waithing,because shes terminal

  7. 1984 told had 9 months to live had stage 4 melanoma in right lower lip, had lip removed with lower chin, then left thumb amputated due to melanoma, then right tibia repaired and replaced, right inside leg muscle removed then 35 in of large bowel removed, never no chemo nothing but surgery and my undying Faith in my Lord and Savior Jesus Christ

  8. How can one become eligible for trials?

  9. Will there be trials in future? Would healthy shorter ends injected among the longer DNA help to change the protein emzym. Could this be also to do with diet trigers or stress or virus triggers? A great find Chun. Thank you.

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