Researchers at the University of Gothenburg have shown how aging changes how lung cancer develops and spreads and have identified a stress-response protein that appears to drive metastasis in older patients. The study, published in the journal Nature, found that lung tumors in older individuals often grow more slowly but are more likely to spread to other organs, a pattern they have linked to increased activity of the protein ATF4. Blocking this pathway reduced tumor spread in experimental models, suggesting a potential new target to prevent cancer spread.
“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,” said senior author Volkan Sayin, PhD, an associate professor at the University of Gothenburg.
While lung cancer primarily affects the elderly, many laboratory studies have used younger animals models. To better reflect the human clinical population, the researchers compared lung tumors in both young and old mice and also examined clinical data from about 1,000 lung cancer patients in Sweden. The tumors in older people were typically smaller and slower growing but more frequently detected at a stage when the disease had already spread.
The study identified a potential culprit for this, a protein called ATF4 which is active in integrated stress response, such as nutrient deprivation or misfolded proteins. The research showed that in older people, lung tumors exploit the stress response pathway to adapt its metabolism in ways that promote metastatic spread of the cancer.
“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,” Sayin said.
In their study, the team showed that tumors from both mice and human patients showed higher levels of ATF4 in older individuals. Elevated levels of the protein were also associated with increased recurrence after lung surgery and poorer survival among patients with lung adenocarcinoma.
“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, PhD, also an associate professor at the University of Gothenburg.
This new research helps provide some answers to the longstanding questions about how aging affects cancer biology. “Lung cancer predominantly affects older individuals, yet how physiological aging influences tumor evolution remains poorly understood,” the researchers noted. “Here we show that aging reprograms the evolutionary trajectory of KRAS-driven lung adenocarcinoma, limiting primary tumor growth while promoting metastatic dissemination through epigenetic activation of the integrated stress response (ISR).”
The findings also help explain what has been an apparent contradiction in lung cancer epidemiology. Earlier research studies have indicated that aging can limit the growth of primary lung tumors, yet lung cancer mortality increases with age. The current findings help explain this by showing that aging both suppresses tumor growth while enabling earlier metastatic spread.
The discovery also highlights a potential therapeutic vulnerability. Sustained ATF4 activity creates dependence on glutamine metabolism, suggesting that targeting this metabolic pathway could limit metastatic spread. In the mouse models used in this study, the team showed that blocking ATF4 signaling or related metabolic processes significantly reduced dissemination of tumors originating in older mice.
The data suggest that measuring ATF4 activity could be used in clinical settings to help identify patients at higher risk of recurrence or metastasis. Tumors with high ATF4 activity may represent a subgroup of patients who could benefit from therapies that target the integrated stress response or glutamine metabolism.
The researchers will now look to determine how aging influences treatment response and resistance. They also plan to investigate therapies that directly target ATF4 or downstream metabolic pathways and explore how age-based patient stratification could be incorporated into clinical trials.
