Respiratory viral infections awaken metastatic breast cancer cells in lungs – Nature

Report on the Impact of Respiratory Viral Infections on Metastatic Cancer Progression and its Alignment with Sustainable Development Goals

Introduction: Addressing Global Health Challenges under SDG 3

In alignment with Sustainable Development Goal 3 (SDG 3), which aims to ensure healthy lives and promote well-being for all at all ages, this report examines the critical intersection of infectious and non-communicable diseases. Breast cancer remains a significant global health burden, with metastatic disease being the primary cause of mortality. A crucial challenge in achieving SDG 3’s target of reducing premature mortality from non-communicable diseases is understanding the mechanisms that trigger metastatic relapse from dormant disseminated cancer cells (DCCs). This report analyzes findings that demonstrate a direct link between common respiratory viral infections, such as influenza and SARS-CoV-2, and the awakening of dormant cancer cells, thereby increasing the risk of metastatic progression and cancer-related death.

Key Findings from Preclinical Models

Viral Infection as a Catalyst for Metastatic Awakening

Experimental studies in mouse models provide compelling evidence that respiratory viral infections can disrupt cancer cell dormancy, a finding with profound implications for global health and SDG 3. The primary observations include:

• Influenza and SARS-CoV-2 Infections: Both influenza A virus (IAV) and a mouse-adapted SARS-CoV-2 strain were shown to trigger the proliferation of dormant breast cancer cells in the lungs.
• Rapid Metastatic Expansion: Following infection, a massive expansion of DCCs into metastatic lesions was observed within weeks, representing a significant acceleration of the metastatic process.
• Relevance Across Models: This phenomenon was consistently observed across multiple breast cancer models, suggesting a fundamental biological mechanism rather than a model-specific artifact.

These findings identify a previously underappreciated risk factor for cancer survivors, highlighting the need for integrated health strategies that consider the impact of infectious diseases on chronic conditions, a core tenet of SDG 3.

Cellular and Molecular Mechanisms Driving Metastasis

The research elucidates a two-phase mechanism by which viral infections promote the reawakening of dormant cancer cells, offering targets for therapeutic innovation in line with SDG 9 (Industry, Innovation, and Infrastructure).

1. Phase 1: IL-6 Dependent Awakening:
   • The initial inflammatory response to viral infection, characterized by high levels of Interleukin-6 (IL-6), is essential for awakening DCCs.
   • In the absence of IL-6, the virus-induced proliferation and expansion of DCCs were significantly diminished.
   • This phase involves a phenotypic transition in cancer cells, which activates pathways related to extracellular matrix remodeling and angiogenesis, preparing the microenvironment for tumor growth.
2. Phase 2: CD4+ T Cell-Mediated Maintenance:
   • Following the initial expansion, CD4+ T cells are recruited to the lungs and are crucial for maintaining the newly awakened cancer cells.
   • These CD4+ T cells were found to suppress the anti-tumor activity of cytotoxic CD8+ T cells, effectively shielding the metastatic cells from immune clearance.
   • Depletion of CD4+ T cells restored the anti-tumor function of CD8+ T cells and led to the elimination of the expanded DCCs.

Human Observational Data and Public Health Implications

Corroborating Evidence from Human Populations

The preclinical findings are strongly supported by analyses of large-scale human health databases, demonstrating the real-world relevance of this mechanism. This synergy between laboratory research and population health data exemplifies the collaborative approach advocated by SDG 17 (Partnerships for the Goals).

• UK Biobank Analysis: An analysis of cancer survivors revealed that a positive SARS-CoV-2 test was associated with a substantially increased risk of cancer-related mortality. The risk was highest in the months immediately following infection, mirroring the rapid metastatic expansion seen in preclinical models.
• Flatiron Health Database Analysis: A separate study of female breast cancer patients showed that a COVID-19 diagnosis was associated with a significantly increased risk of subsequent progression to metastatic lung disease.

Alignment with Sustainable Development Goals

SDG 3: Good Health and Well-being

This research directly contributes to achieving the targets of SDG 3 by:

• Identifying a significant risk factor that contributes to premature mortality from cancer.
• Providing a scientific basis for developing new public health strategies to protect cancer survivors, a vulnerable population, from the consequences of common infections.
• Highlighting the necessity of integrating infectious disease prevention and management into comprehensive cancer care plans.

SDG 17: Partnerships for the Goals

The study serves as a model for SDG 17 by leveraging multi-sectoral partnerships. The combination of academic research, international collaboration, and the use of large-scale public (UK Biobank) and private (Flatiron Health) data resources was essential to connect molecular mechanisms with population-level outcomes, demonstrating a powerful framework for addressing complex global health issues.

Conclusion and Recommendations

The evidence strongly indicates that respiratory viral infections are a significant trigger for metastatic cancer recurrence. This link poses a substantial threat to the long-term health and well-being of millions of cancer survivors worldwide, directly impacting the global community’s ability to meet the targets of SDG 3.

Recommendations for Action

Based on these findings, the following actions are recommended:

1. Enhance Public Health Strategies: Public health initiatives should prioritize the protection of cancer survivors from respiratory viral infections through targeted vaccination campaigns and awareness programs.
2. Advance Clinical Research and Interventions: Clinical studies should be initiated to evaluate the efficacy of interventions, such as IL-6 receptor antagonists or JAK inhibitors, in cancer survivors with severe respiratory infections to mitigate the risk of metastatic progression. This aligns with fostering innovation under SDG 9.
3. Promote Integrated Care Models: Healthcare systems should develop integrated care pathways that bridge oncology and infectious disease management to provide holistic care for cancer survivors.
4. Foster Global Research Collaboration: Continued support for international and multi-disciplinary partnerships, as championed by SDG 17, is crucial for further elucidating the interplay between infectious agents and non-communicable diseases.

Analysis of Sustainable Development Goals (SDGs) in the Article

1. Which SDGs are addressed or connected to the issues highlighted in the article?

1. SDG 3: Good Health and Well-being

   • The article’s central theme is the intersection of communicable diseases (influenza, SARS-CoV-2) and non-communicable diseases (breast cancer). It directly investigates health outcomes, specifically cancer progression and mortality, which is a core component of SDG 3. The research explores how respiratory infections, a major global health concern, can worsen the prognosis for cancer survivors, highlighting a critical link between different health challenges.

2. SDG 9: Industry, Innovation, and Infrastructure

   • The study is a clear example of advanced scientific research and innovation. The methods section details the use of sophisticated techniques like “Fixed single-cell RNA-seq,” “bulk RNA-seq,” and complex transgenic mouse models. This type of research is fundamental to enhancing scientific capabilities, a key aspect of SDG 9, as it drives new understanding and potential therapeutic interventions.

3. SDG 17: Partnerships for the Goals

   • The research was conducted through a multi-institutional and international collaboration, as evidenced by the author affiliations from the USA, UK, and the Netherlands. Furthermore, the study relies on large-scale data sharing, utilizing the “UK Biobank” and the “Flatiron Health electronic health record (EHR) database.” This demonstrates effective public, private, and academic partnerships to address a complex global health issue, aligning with the principles of SDG 17.

2. What specific targets under those SDGs can be identified based on the article’s content?

1. Under SDG 3: Good Health and Well-being

   • Target 3.4: By 2030, reduce by one third premature mortality from non-communicable diseases through prevention and treatment and promote mental health and well-being.
     • The article directly addresses this target by investigating a mechanism that increases mortality from breast cancer, a major non-communicable disease. It states that “SARS-CoV-2 infection substantially increases the risk of cancer-related mortality” and that “death rates from cancer rose in the first two years of the COVID-19 pandemic.” Understanding this link is crucial for developing strategies to prevent this premature mortality in cancer survivors.
   • Target 3.d: Strengthen the capacity of all countries, in particular developing countries, for early warning, risk reduction and management of national and global health risks.
     • The research provides critical insights into a previously under-recognized health risk associated with the COVID-19 pandemic. The finding that respiratory viral infections can “trigger the development of metastases from dormant DCCs” serves as an early warning for the long-term health management of millions of cancer survivors globally, informing risk reduction strategies.

2. Under SDG 9: Industry, Innovation, and Infrastructure

   • Target 9.5: Enhance scientific research, upgrade the technological capabilities of industrial sectors in all countries… including… encouraging innovation and substantially increasing the number of research and development workers.
     • This article is a product of enhanced scientific research. It employs cutting-edge methodologies to “offer new insights into the connection between infectious diseases and cancer metastasis.” Such research contributes to the global body of scientific knowledge and represents the kind of innovation needed to tackle complex health problems.

3. Under SDG 17: Partnerships for the Goals

   • Target 17.16: Enhance the global partnership for sustainable development, complemented by multi-stakeholder partnerships that mobilize and share knowledge, expertise, technology and financial resources.
     • The study exemplifies this target through its international collaboration and use of shared data resources. The analysis of data from the “UK Biobank” and the US-based “Flatiron Health database” represents a mobilization and sharing of knowledge and data across borders to achieve a common research goal.

3. Are there any indicators mentioned or implied in the article that can be used to measure progress towards the identified targets?

1. For SDG 3 Targets

   • Indicator 3.4.1 (Mortality rate attributed to… cancer): The article provides direct data relevant to this indicator. It reports an “odds ratio of 1.85” for increased cancer mortality in SARS-CoV-2 positive cancer survivors from the UK Biobank data. It also reports a “hazard ratio of 1.44… for subsequent diagnosis of metastatic breast cancer in the lungs” from the Flatiron Health database. These statistics are direct measures of cancer-related mortality and progression risk.
   • Indicator for Target 3.d (e.g., preparedness for health risks): The article provides data that can be used to build indicators for health risk management. The quantification of increased metastatic burden (a “100–1,000-fold” increase in metastatic burden in mice post-infection) and the identification of IL-6 as a key mediator provide measurable biological markers and risk factors that could be monitored in cancer survivor populations to manage the risk of recurrence post-infection.

2. For SDG 9 Targets

   • Indicator 9.5.1 (Research and development expenditure as a proportion of GDP): While not stating expenditure directly, the article is an output of such investment. The highly specialized research involving “scRNA-seq,” “transgenic mouse models,” and analysis of massive epidemiological datasets implies significant R&D expenditure and serves as a qualitative indicator of investment in scientific innovation.

3. For SDG 17 Targets

   • Indicator 17.16.1 (Number of countries reporting progress in multi-stakeholder development effectiveness monitoring frameworks): The article itself is evidence of a successful multi-stakeholder partnership. The collaboration between academic institutions in the US, UK, and Netherlands, and the use of data from both public (UK Biobank) and private (Flatiron Health) sources, serves as a case study and an implicit indicator of effective partnerships in action.

4. Table of SDGs, Targets, and Indicators

Source: nature.com