Researchers identify gene pairing that helps melanoma cells keep dividing
A Pitt-led study says TPP1 mutations work with TERT mutations to lengthen telomeres, a survival mechanism common in melanoma tumors.
By Lucas Ferreira · Science & Environment Writer
3 min read
University of Pittsburgh researchers say they have identified a genetic combination that helps melanoma cells extend their lifespan and keep growing. The finding matters because it points to a cancer-specific telomere system that researchers say could be explored as a future treatment target.
Jonathan Alder, an assistant professor at the University of Pittsburgh School of Medicine, and colleagues reported in Science that mutations affecting two genes, TERT and TPP1, can work together to produce the unusually long telomeres seen in melanoma tumors. The university said the work helps explain a long-running question in melanoma biology.
Telomeres are protective structures at the ends of chromosomes. According to the researchers, telomeres shorten as healthy cells divide, and once they become too short, cells lose the ability to keep dividing.
That limit is one of the barriers a normal cell must cross before becoming cancerous, Alder said. The University of Pittsburgh said melanoma has stood out because its tumors often carry exceptionally long telomeres compared with many other cancers.
The enzyme telomerase can lengthen telomeres. Pitt said most healthy cells do not keep telomerase active, while many cancers switch it on through mutations in TERT, a gene tied to telomerase production and activity.
Melanoma depends heavily on that route, according to the university. About 75% of melanoma tumors have TERT mutations that raise telomerase production and activity, Pitt said.
But the TERT finding did not fully solve the problem. Researchers could add TERT mutations to melanocytes, the pigment-producing cells from which melanoma arises, but still not recreate the very long telomeres found in melanoma tumors, according to the university.
Pattra Chun-on, an internist pursuing a Ph.D. in Alder’s lab, investigated what else was involved. Pitt said earlier work from Alder’s group had found recurring mutations in cancer databases in TPP1, a protein that binds telomeres.
Chun-on found that the TPP1 mutations resembled the TERT mutations in a key way, according to Pitt. They appeared in the newly annotated promoter region of TPP1 and increased production of the protein.
That result fit with previous biochemical research showing that TPP1 can increase telomerase activity, Alder said. Pitt said the new study connected that laboratory observation to changes seen in melanoma.
Chun-on then introduced mutated versions of both TERT and TPP1 into cells. The university said the pair generated the long telomeres associated with melanoma tumors, showing that TPP1 was the missing factor needed to explain the effect.
The study does not report a new melanoma drug. Pitt said it identifies a telomere-maintenance mechanism specific to cancer cells, which may give researchers a clearer target as they look for ways to interfere with melanoma growth.
Additional study authors were affiliated with Pitt, UPMC, the University of California, Santa Cruz, and Johns Hopkins University. The work was supported by National Institutes of Health grants R35CA209974 and R01HL135062, according to the university.
This story draws on original reporting from ScienceDaily.