Roughly 75 percent of melanoma tumors carry a mutation in the TERT gene, and yet that mutation was never enough on its own. When researchers put TERT mutations into pigment cells in the lab, the cells still failed to grow the unusually long telomeres seen in real melanoma. Something else was missing.
A team at the University of Pittsburgh School of Medicine reports in Science that it has found the missing piece: a mutated telomere-binding protein called TPP1. The senior researcher is Jonathan Alder, PhD, an assistant professor in the Division of Pulmonary, Allergy and Critical Care Medicine.
Why telomeres matter
Telomeres are protective caps on the ends of chromosomes. Each time a healthy cell divides they shrink, and eventually they get too short for the cell to divide again. Telomeres that become too short can cause disorders linked to premature aging and early death. Unusually long ones are often associated with cancer.
The enzyme telomerase rebuilds telomeres. It stays inactive in most healthy cells, but many cancers switch it on through TERT mutations. Melanoma tumors have long been known to carry exceptionally long telomeres compared with many other cancers.
“There’s some special link between melanoma and telomere maintenance,” Alder said. “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.”
A hunch that would not go away
Pattra Chun-on, M.D., an internist pursuing her Ph.D. in Alder’s lab, took on the question. Alder’s laboratory had already spotted frequent TPP1 mutations while searching cancer mutation databases. Chun-on found that they closely resembled the TERT mutations. They sit in a newly annotated promoter region of the TPP1 gene and increase production of the protein.
That mattered because biochemists had shown more than a decade earlier that TPP1 raises telomerase activity in a test tube. “We never knew that this actually happened clinically,” Alder said.
Chun-on introduced mutated forms of both TERT and TPP1 into cells. Together, the two produced the very long telomeres that mark melanoma tumors. Alder called TPP1 the long-sought factor, “hidden in plain sight.”
He also remembers how she got into his lab. She wanted to study cancer, and he told her he studied short telomeres, not long ones. “This went on until I realized that Pattra would never take ‘no’ for an answer,” Alder said.
The findings give a new account of how melanoma develops and survives, and they point to a cancer-specific system for maintaining telomeres that could become a target for future therapies. No treatment based on it exists yet. Anyone worried about a mole or skin change should see their doctor.
The work was supported by National Institutes of Health grants R35CA209974 and R01HL135062.
