Respiratory infections activate dormant breast cancer cells in the lungs

Researchers from the University of Colorado Anschutz Medical Campus, Montefiore Einstein Comprehensive Cancer Center (MECCC) and Utrecht University have found the first direct evidence that common respiratory infections, including COVID-19 and influenza, can “wake up” dormant breast cancer cells that have spread to the lungs, setting the stage for new metastatic tumors to emerge.

The findings, published in the journal Nature, were obtained in mice and are supported by studies showing increased mortality and lung metastases among cancer survivors infected with SARS-CoV-2, the virus that causes COVID-19.

“Our findings suggest that people with a history of cancer may benefit from taking precautions against respiratory viruses, such as vaccination (if available), and discussing potential risks with their healthcare providers,” said Julio Aguirre-Guiso, Ph.D., co-lead author of the study, director of the Cancer Sleep Institute at MECCC, professor of cell biology, oncology, and medicine, and holder of the Rose Falkenstein Chair in Cancer Research at the Albert Einstein College of Medicine.

The study was led by James DeGregory, Ph.D., associate director of the University of Colorado Cancer Center. Co-leaders include Mercedes Rincon, Ph.D. (CU Anschutz) and Roel Verheulen, Ph.D. (Utrecht University, The Netherlands, and Imperial College London).

"This is a complex and multidisciplinary study that really required a team effort," said Dr. DeGregori.

Awakening 'sleeping cells' in mice

Before this study, there was some evidence that inflammatory processes could “wake up” disseminated cancer cells (DCCs). These are cells that have broken away from the primary tumor and spread to distant organs, often remaining dormant for long periods of time.

“During the COVID-19 pandemic, there have been isolated reports suggesting a possible increase in cancer mortality, strengthening the hypothesis that severe inflammation may promote the activation of dormant DCCs,” said Dr. Aguirre-Guiso, who also leads the Tumor Microenvironment and Metastasis Research Program at MECCC.

The scientists tested this hypothesis using unique mouse models of metastatic breast cancer developed in Dr. Aguirre-Guiso’s lab. These models include dormant DCCs in the lungs and therefore closely mimic an important aspect of the disease in humans.

Mice were exposed to SARS-CoV-2 or influenza viruses. In both cases, respiratory infections led to the awakening of dormant DCCs in the lungs, which caused a massive growth of metastatic cells within days of infection and the emergence of metastatic foci within two weeks.

"Dormant cancer cells are like the embers left behind by an abandoned fire, and respiratory viruses are like a strong wind fanning the flames," Dr. DeGregori said.

Molecular analysis showed that activation of dormant DCCs is triggered by interleukin-6 (IL-6), a protein released by immune cells in response to infection or injury.

“The discovery of IL-6 as a key mediator of DCCs awakening from dormancy suggests that the use of IL-6 inhibitors or other targeted immunotherapies may prevent or attenuate metastatic recurrence after viral infection,” said Dr. Aguirre-Guiso.

Two population studies also confirm the risk to humans

The COVID-19 pandemic has provided a unique opportunity to study the impact of respiratory viruses (in this case, SARS-CoV-2) on cancer progression. The team analyzed two large data sets and found support for their hypothesis: respiratory infections in patients in remission are associated with metastatic progression.

The first study used the UK Biobank, a population-based cohort of more than 500,000 participants, some of whom had already been diagnosed with cancer before the pandemic. Researchers from Utrecht University and Imperial College London looked at whether COVID-19 infection increased the risk of cancer death in these people. They focused on cancer survivors who had been diagnosed at least five years before the pandemic, meaning they were likely to be in remission. Of these, 487 people tested positive for COVID-19 and were matched with 4,350 controls who tested negative.

After excluding patients who died from COVID-19, the researchers found that cancer patients who had COVID-19 were nearly twice as likely to die from cancer as those who did not have COVID-19.

“This effect was most pronounced during the first year after infection,” Dr. Verheulen said. The rapid tumor progression in people matched the dramatic growth of dormant cancer cells seen in animal models.

In a second population-based study using the Flatiron Health (USA) database, researchers Junxiao Hu and Dexiang Gao analyzed data on breast cancer patients seen in 280 oncology clinics. They compared the incidence of lung metastasis among patients who did not have COVID-19 (36,216) and those who had (532). Over 52 months of follow-up, those who had COVID-19 had an almost 50% higher risk of developing lung metastases than patients with the same diagnosis without COVID-19.

“Our findings suggest that cancer survivors may have an increased risk of relapse with metastasis after common respiratory viral infections,” said Dr. Verheulen. “It is important to note that our study was conducted before the availability of COVID-19 vaccines.”

“By understanding the underlying mechanisms, we will aim to develop interventions that can limit the risk of metastatic progression in cancer survivors who have had respiratory viral infections,” said Dr. DeGregori. “We also plan to expand our studies — both in animal models and by analyzing clinical data — to other cancer types and other organs that are affected by metastases. Respiratory viral infections are here to stay, so we need to understand their long-term consequences.”