Respiratory viral infection promotes the awakening and outgrowth of dormant metastatic breast cancer cells in lungs [RNA-seq]
Breast cancer is the second most common cancer globally, with most deaths caused by metastatic disease, often following long periods of clinical dormancy1. Understanding the mechanisms that disrupt the quiescence of dormant disseminated cancer cells (DCC) is crucial for addressing metastatic progression. Respiratory viruses infections such as influenza or SARS-CoV-2, trigger both local and systemic inflammation2,3. Here we demonstrate that influenza virus and SARS-CoV-2 infections lead to loss of the pro-dormancy phenotype in breast DCC in the lung, causing DCC proliferation within days of infection, and a massive expansion of carcinoma cells into metastatic lesions within two weeks. This phenotypic transition and expansion are interleukin-6 (IL-6)-dependent. We show that CD4+ T cells sustain pulmonary metastatic burden post-influenza infection by suppressing CD8+ T cell responses. Additionally, DCCs impair lung T-cell activation and tumor cell killing in infected mice. Critically, these experimental findings align with human observational data. Analyses of cancer survivors from the UK Biobank and Flatiron Health databases reveal that SARS-CoV-2 infection substantially increases the risk of lung metastasis and cancer-related mortality compared to uninfected cancer survivors. Notably, the heightened risk is most pronounced in the months following infection, paralleling experimental observations of accelerated DCC proliferation and metastatic progression shortly after viral infection. These discoveries underscore the significant impact of respiratory viral infections on metastatic cancer resurgence, offering novel insights into the interconnection between infectious diseases and cancer metastasis. Overall design: MMTV-Her2 mice were given PBS or influenza A virus through intranasal administration. Lungs were harvested 9dpi, single cell suspsension were generated, Her2+ cells were FACS-sorted.