Telomeres are repeated DNA sequences that form the end caps of chromosomes. A little of their length is lost with each cell division, and cells self-destruct or become senescent and cease replication when telomeres become too short. This is a part of the Hayflick limit on cell replication: near all cells in the body can only divide a limited number of times. Stem cells are the first exception, using telomerase to extend telomeres. Cancer cells are the second exception, employing either telomerase or the alternative lengthening of telomeres (ALT) mechanisms that do not operate in normal cells. Telomere lengthening is a universal mechanism in cancer, and thus there is considerable interest in producing a single class of treatment, based on interference in telomere lengthening, that can potentially shut down all cancers.
The original vision for whole-body interdiction of telomere lengthening, a part of the SENS rejuvenation research agenda, was to turn off the processes that lengthen telomeres throughout the body. Perhaps temporarily, or, in a more futuristic option, perhaps permanently when deployed in conjunction with periodic replacement of stem cell populations. Since the original proposition was put forward, research into ALT hasn't made all that much progress, perhaps because only 10% of cancers exhibit this behavior. Research into interfering with telomerase-based telomere lengthening has progressed, however, and diversified into a number of interesting lines of work. All of these seem likely to be targeted to cancer cells, either as an inherent result of the mechanism, or by combining the therapy with a selective delivery system.
One recent example of many is the work of Maia Biotechnology, building on an approach that sabotages telomerase-based telomere lengthening in a subtle way that has the outcome of killing cells. Today's research materials are another example of a program at an earlier stage of exploration, more focused on an indirect approach to reducing telomerase activity, one that can involve signaling applied outside the cell. This makes it an attractive basis for the development of therapies.
Researchers have in the past provided evidence to suggest that shelterins, proteins that wrap around telomeres and act as a protective shield, might be therapeutic targets for cancer treatment. Subsequently, they found that eliminating one of these shelterins, TRF1, blocks the initiation and progression of lung cancer and glioblastoma in mouse models and prevents glioblastoma stem cells from forming secondary tumours. Now researchers go one step further and describe for the first time how telomeres can be regulated by signals outside the cell that induce cell proliferation and have been implicated in cancer. The finding opens the door to new therapeutic possibilities targeting telomeres to help treat cancer.
Researchers have outlined a link between TRF1 and the PI3K/AKT signalling pathway. This metabolic pathway, which also encompasses mTOR, is one of the pathways most frequently affected in numerous tumorigenic processes. However, it was not known whether preventing TRF1 regulation by this pathway can have an impact on telomere length and its ability to form tumours. AKT acts as a transmitter of extracellular signals triggered by, among others, nutrients, growth factors, and immune regulators, to the interior of cells.
Researchers modified the TRF1 protein in cells to make it unresponsive to AKT, using the gene-editing tool CRISPR/Cas9. This way, TRF1 and the telomeres became invisible to any extracellular signals transmitted by AKT. Telomeres in these cells shortened and accumulated more damage; most importantly, the cells were no longer able to form tumours, indicating that telomeres are important targets of AKT and its role in cancer development.
The paper shows that telomeres are among the most important intracellular targets of the AKT pathway to form tumours, since, although neither the function of AKT nor of any of the thousands of proteins that are regulated by it was altered, only blocking AKT's ability to modify telomeres was sufficient to slow tumour growth. The next step will be to generate genetically modified mice with telomeres that are invisible to AKT. The authors anticipate that these mice will be more resistant to cancer.
The telomere-bound shelterin complex is essential for chromosome-end protection and genomic stability. Little is known on the regulation of shelterin components by extracellular signals including developmental and environmental cues. Here, we show that human TRF1 is subjected to AKT-dependent regulation. To study the importance of this modification in vivo, we generate knock-in human cell lines carrying non-phosphorylatable mutants of the AKT-dependent TRF1 phosphorylation sites by CRISPR-Cas9.
We find that TRF1 mutant cells show decreased TRF1 binding to telomeres and increased global and telomeric DNA damage. Human cells carrying non-phosphorylatable mutant TRF1 alleles show accelerated telomere shortening, demonstrating that AKT-dependent TRF1 phosphorylation regulates telomere maintenance in vivo. TRF1 mutant cells show an impaired response to proliferative extracellular signals as well as a decreased tumorigenesis potential. These findings indicate that telomere protection and telomere length can be regulated by extracellular signals upstream of PI3K/AKT activation, such as growth factors, nutrients, or immune regulators, and this has an impact on tumorigenesis potential.