New protein target for safer lung cancer therapy

Researchers at the University of Gothenburg have identified a protein linked to an increased risk of metastasis and recurrence in lung cancer. The findings are presented in a study that paves the way for new precision medicine approaches, particularly for older patients.

Lung cancer primarily affects older individuals. Despite this, many laboratory studies rely on experimental animal models using young animals.

To better reflect the reality of the disease, the researchers compared lung tumors in young and old mice. In addition, they analyzed data from around one thousand lung cancer patients in the Swedish regions of Halland and Västra Götaland.

The results, published in the journal Nature, reveal clear patterns. In older individuals, tumors were often smaller and grew more slowly. At the same time, the disease was more advanced when detected and more frequently had spread to other organs.

This helps explain a paradox that physicians often observe that older patients may be diagnosed with a small and slowly growing primary tumor that has nevertheless already spread far beyond the lung, for example to the brain, liver, and bones."

Volkan Sayin, Associate Professor, University of Gothenburg

A hijacked stress-response system

The study shows how aging alters the biology of lung cancer and makes tumors more prone to spreading. The researchers identified a molecular signaling pathway, a complex chain of reactions and interactions, in which a specific stress-response protein, ATF4, plays a central role.

Under normal physiological conditions, ATF4 acts as a hub for the "integrated stress response" that responds to events such as nutrient deprivation, viral particles, or the accumulation of misfolded proteins, activating protective and corrective responses, explains Volkan Sayin.

"In older patients, this stress response is hijacked by the tumor, allowing cancer cells to reprogram their metabolism. The tumor does not grow faster, but this metabolic rewiring enables the cancer cells to spread and form metastases in other parts of the body," he says.

Tumors from older individuals in the study, both mice and humans, showed higher levels of ATF4. High ATF4 levels were also associated with increased recurrence after lung surgery and poorer survival among patients with lung adenocarcinoma, the most common form of lung cancer.

"Our results suggest that ATF4 is not only part of the mechanism behind the spread of lung cancer but may also serve as a marker of more aggressive disease," says Clotilde Wiel, Associate Professor at the University of Gothenburg.

A new treatment strategy

The study opens the door to a treatment strategy targeting the age-related signaling system that the tumor has hijacked. By blocking ATF4, or a specific metabolic process controlled by ATF4, with drugs, the researchers were able to dramatically reduce the spread of old tumors in mice.

Previously, it has been unclear why studies using similar drugs have largely failed when tested in humans. The new findings suggest that these treatments may need to be targeted more precisely to the right patient groups.

"Our results indicate that these drugs may work significantly better if used more precisely, for example in older patients whose tumors show high ATF4 activity," says Clotilde Wiel.

Biological aging overlooked

Treatments such as chemotherapy and radiation therapy are primarily aimed at rapidly growing tumors, which are not the type of lung tumors most common in older patients. According to the researchers, research and drug development in general need to take biological aging more into account.

"It is very clear that normal aging fundamentally changes how tumors develop, a field of research where we currently lack a lot of knowledge. Indeed, relatively little cancer research is conducted in age-appropriate models, as such studies are both very expensive and take a long time," concludes Volkan Sayin.