Melanoma Maneuvers Mortality by Maintaining Telomeres

It may appear counter-intuitive but overcoming death is a key step in the journey of a cell toward cancer.

A study published in the journal Science shows malignant melanocytes—melanin-producing cells in the skin—accomplish this feat in two conspiring steps that activate expressions of telomerase and a peptidase called tripeptidyl peptidase 1 (TPP1). Mutations in TPP1 and telomerase synergistically lengthen the protective caps at chromosomal ends (telomeres), preventing the normal process of replicative senescence which allows cells to age with every cycle of replication and eventually die due to shortened telomeres. Short telomeres are a sign of cellular aging, but extra-long telomeres are associated with cancer.

“There’s some special link between melanoma and telomere maintenance,” said Jonathan Alder, PhD, an assistant professor of medicine at the University of Pittsburgh School of Medicine, who is the senior author of the study. “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.”

Identifying the exact combination of mutations in melanoma that prevents death and achieves explosive, indefinite growth could change the way clinicians understand and treat melanoma.

Telomerase is inactive in most cells, but many cancers acquire mutations in the telomerase gene, TERT, that activate telomerase and allow cells to keep growing. Nearly 75% of melanomas harbor mutations in TERT. Yet, experimentally inserting TERT mutations in melanocytes does not produce the long telomeres seen in melanoma patients. Turns out that TERT promoter mutations are just half of the story.

Pattra Chun-on, MD, an internist earning her PhD in Alder’s lab was determined to find the missing link that maintained long telomeres in melanoma. In earlier studies, Alder’s team had discovered a region in the telomere binding protein TPP1, which was often mutated in melanoma tumors. Mutations in the TPP1 promoter occur in about 5% of skin melanoma and co-occur with mutations in the TERT promoter.

Chun-on found that the mutations in TPP1 resembled those in TERT. Both sets of mutations were located in the promoter regions of the respective genes. The mutations create or modify binding sites of transcription factors called E-twenty-six (ETS) that stimulated the expression of the gene product.

Adler found this intriguing because TPP1 was 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.

Chun-on mutated genes for both telomerase and TPP1 in cells and observed distinctively long telomeres as seen in melanoma tumors. TPP1 was the missing factor that maintained extra-long telomeres in a melanoma cell.

That changes in the TPP1 promoter collaborate with TERT activation to maintain long telomeres immortalize melanoma cells increases our understanding of the telomere maintenance system in cancer and has the potential to improve treatments for cancer.