CNIO researchers show that targeting telomeres might be an effective therapeutic strategy against lung cancer

Healthy cells can only divide a limited number of times during an organism’s lifetime. In contrast, tumor cells are immortal: they proliferate indefinitely and uncontrollably, and this is the defining characteristic of cancer. Researchers from the Telomeres and Telomerase Group at the CNIO (Spanish National Cancer Research Center), led by Maria Blasco, have studied for the first time the possibility of treating lung cancer by targeting the telomeres, the structures that protect the ends of chromosomes and whose condition determines the cell’s ability to divide indefinitely.

The results, as explained by the researchers in the journal Cell Death & Differentiation, show that, indeed, targeting telomeres “might be an effective therapeutic strategy” against non-small cell lung cancer, which is responsible for much of the mortality in lung cancer patients.

The work has Sergio Piñeiro as first author, recipient of a postdoctoral contract from the Spanish Association Against Cancer (AECC).

“Removing immortality from cancer cells is a therapeutic strategy that has not yet been exploited in the fight against cancer,” says Maria Blasco.

Focus on the tumor microenvironment

Lung cancer is one of the leading causes of cancer death. The long-term ineffectiveness of current therapies and late diagnosis mean that only one in five patients survive more than five years. Specifically, non-small cell lung cancer is responsible for 85% of lung cancer-associated deaths.

The work now published focuses on the so-called tumor microenvironment, which is a set of cells and factors surrounding the tumor that plays a crucial role in the development of cancer and the response to therapies.

The researchers analyzed the impact of dysfunctional telomeres. Also, they studied the effect of telomerase deficiency on the cellular microenvironment of non-small cell lung tumors, telomerase being the enzyme that repairs telomeres.

Telomerase deficiency

Telomeres are protein structures located at the ends of chromosomes. At each cell division, telomeres shorten until, after a certain number of divisions, the shortening becomes excessive and the cell stops dividing. This happens in healthy cells, but not in most tumor cells.

Telomerase expression is reactivated in 90% of human tumors. Because of the action of telomerase, the telomeres in tumor cells maintain a minimum functional length, which allows them to divide indefinitely.

CNIO researchers studied what happened when they caused a telomerase deficit in the lung tumor microenvironment. They also deliberately damaged their telomeres, using the compound 6-thio-dG.

“It is the first time that the involvement of telomerase and dysfunctional telomeres in the lung tumor microenvironment has been investigated,” explains Sergio Piñeiro, currently at the Spanish National Research Council (CSIC) in La Rioja.

Damaged telomeres hold back the tumor

Telomerase deficiency and dysfunctional telomeres slowed tumor progression. The researchers observed a reduction in tumor implantation and vascularization in the lung, while increasing the vulnerability of tumors to DNA damage and cell death. Tumor cell proliferation and inflammation were also decreased, and the anti-tumor response of the immune system was enhanced. As the authors write in Cell Death & Differentiation, “we address by the first time the implication of TERT [telomerse] and dysfunctional telomeres in the lung tumor microenvironment. Our results demonstrate that targeting telomeres might be an effective therapeutic strategy in non-small cell lung cancer”.

Reference article: Piñeiro-Hermida, S., Bosso, G., Sánchez-Vázquez, R. et al. Telomerase deficiency and dysfunctional telomeres in the lung tumor microenvironment impair tumor progression in NSCLC mouse models and patient-derived xenografts. Cell Death Differ (2023). https://doi.org/10.1038/s41418-023-01149-6

Image: CNIO Telomeres and Telomerase Group - Humanism and Science Foundation. Sergio Piñeiro is standing, second from left. Maria Blasco is fifth from the left, standing. / Laura M. Lombardía. CNIO.