How cancer cells can become immortal - new research finds mutated gene that helps melanoma overcome normal limits of repeated replication

How cancer cells can become immortal – new research finds mutated gene that helps melanoma overcome normal limits of repeated replication

A defining characteristic of cancer cells is their immortality. Usually normal cells are limited in the number of times they can divide before they stop growing. Cancer cells, however, can overcome this limitation to form tumors and circumvent “death” by continuing to replicate.

Telomeres play a vital role in determining the number of times a cell can divide. These repetitive DNA sequences are located at the ends of chromosomes, structures that contain genetic information. In normal cells, continuous cycles of replication shorten telomeres until they become so short that they eventually trigger the cell to stop replicating. In contrast, tumor cells can maintain the length of their telomeres by activating an enzyme called telomerase which rebuilds telomeres during each replication.

Diagram of the chromosome with red telomeres at the ends
Telomeres are protective caps at the ends of chromosomes.
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Telomerase is encoded by a gene called TERT, one of the most frequently mutated genes in cancer. TERT mutations cause cells to make a little too much telomerase and are thought to help cancer cells retain their telomeres for a long time even though they are replicating at high rates. Melanoma, an aggressive form of skin cancer, relies heavily on telomerase to grow, and three quarters of all melanomas acquire telomerase mutations. These same TERT mutations also occur in other types of cancer.

Unexpectedly, the researchers found that TERT mutations could only partially explain telomere longevity in melanoma. While TERT mutations did extend the lifespan of cells, they did not make them immortal. That meant there had to be something else helping telomerase to allow cells to grow out of control. But what that “second shot” might be is unclear.

We are researchers studying the role telomeres play in human health and diseases like cancer at the University of Pittsburgh’s Alder Lab. By investigating the ways in which tumors maintain their telomeres, we and our colleagues found another piece of the puzzle: another telomere-associated gene in melanoma.

Cancer is the result of uncontrollable cell growth.

Cellular immortality is boosted

Our team focused on melanoma because this type of cancer is linked to people with long telomeres. We examined DNA sequencing data from hundreds of melanoma patients, looking for mutations in genes related to telomere length.

We have identified a group of mutations in a gene called TPP1. This gene codes for one of six proteins that form a molecular complex called shelterin that coats and protects telomeres. Even more interesting is the fact that TPP1 is known to activate telomerase. Identifying the connection of the TPP1 gene to cancer telomeres was, in a way, obvious. After all, over a decade ago researchers showed that TPP1 would increase telomerase activity.

We tested whether an excess of TPP1 could make cells immortal. When we introduced only the TPP1 proteins into the cells, there was no change in cell death or telomere length. But when we introduced the TERT and TPP1 proteins at the same time, we found that they worked synergistically to cause significant telomere elongation.

To confirm our hypothesis, we then inserted TPP1 mutations into melanoma cells using CRISPR-Cas9 genome editing. We found an increase in the amount of TPP1 protein made by the cells and a subsequent increase in telomerase activity. Finally, we returned to DNA sequencing data and found that 5% of all melanomas had a mutation in both TERT and TPP1. Although this is still a significant proportion of melanomas, there are likely other factors that contribute to the maintenance of telomeres in this cancer.

Our findings imply that TPP1 is likely one of the missing pieces of the puzzle that enhances 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, researchers could also block them and potentially prevent telomeres from lengthening and causing cancer cells to die. This finding not only offers scientists another potential avenue for cancer treatment, but also draws attention to an underappreciated class of mutations outside the traditional gene boundaries that may play a role in cancer diagnosis.

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