A defining feature of cancer cells is their immortality. Usually, normal cells are limited in the number of times they can divide before they stop growing. However, cancer cells can overcome this limitation to form tumors and evade “mortality” by continuing to replicate.
Telomeres play an essential role in determining how many times a cell can divide. These repeating DNA sequences are located at the ends of chromosomes, structures that contain genetic information. In normal cells, continuous rounds of replication shorten telomeres until they become so short that they eventually trigger the cell to stop replicating. Tumor cells, on the other hand, can maintain the length of their telomeres by activating an enzyme called telomerase which rebuilds telomeres during each replication.
Telomerase is encoded by a gene called TERT, one of the most commonly mutated genes in cancer. TERT mutations cause cells make a little too much telomerase and are thought to help cancer cells keep their telomeres long, even as they replicate at high rates. Melanomaan aggressive form of skin cancer, relies heavily on telomerase to grow, and three quarters of all melanomas get mutations in telomerase. These same TERT mutations are also ubiquitous other types of cancer.
Unexpectedly, researchers found that TERT mutations could only partially explain the longevity of telomeres in melanoma. While TERT mutations did indeed extend the lifespan of cells, they did not make them immortal. That meant there had to be something else that helps telomerase keep cells from growing out of control. But what that “second hit” might be is unclear.
We are researchers studying the role telomeres play human health and diseases Like it cancer in the Alder Lab at the University of Pittsburgh. While investigating the ways in which tumors retain their telomeres, we and our colleagues found another piece of the puzzle: another telomere-associated gene in melanoma.
Cell immortality gets a boost
Our team focused on melanoma because this type of cancer is linked to people with melanoma long telomeres. We examined DNA sequencing data from hundreds of melanomas, looking for mutations in genes related to telomere length.
We identified a cluster of mutations in a gene called TPP1. This gene codes for one of six proteins that form a molecular complex called take shelter that covers and protects telomeres. Even more interesting is the fact that TPP1 is known activate telomerase. Identifying the connection of the TPP1 gene to cancer telomeres was, in a sense, obvious. After all, that was it more than ten years ago that researchers showed that TPP1 would increase telomerase activity.
We tested whether an excess of TPP1 can make cells immortal. When we introduced only TPP1 proteins into cells, there was no change in cell death or telomere length. But when we introduced TERT and TPP1 proteins at the same time, we found that they acted synergistically to cause significant telomere elongation.
To confirm our hypothesis, we next inserted TPP1 mutations into melanoma cells using CRISPR-Cas9 genome editing. We saw an increase in the amount of TPP1 protein the cells made, and a subsequent increase in telomerase activity. Finally, we returned to the DNA sequencing data and found that 5% of all melanomas have a mutation in both TERT and TPP1. While this is still a significant proportion of melanomas, there are likely other factors that contribute to telomere preservation in this cancer.
Our findings imply that TPP1 is likely one of the missing puzzle pieces that enhance telomerase’s ability to maintain telomeres and support tumor growth and immortality.
Make cancer deadly
Knowing that cancer uses these genes in their replication and growth means researchers can also block them and potentially prevent telomeres from lengthening and making cancer cells deadly. This discovery not only provides scientists with a new avenue for cancer treatment, but also draws attention to an underappreciated class of mutations beyond the traditional boundaries of genes that may play a role in cancer diagnosis.
Patra Chun On, Ph.D. Candidate in Environmental and Occupational Health, University of Pittsburgh Health Sciences and Jonathan ElsAssistant Professor of Medicine, University of Pittsburgh Health Sciences