Abstract Summary

We find that intratumoural bacteria may play a functional role in the Warburg effect in patients with lung cancer. Specifically, we identify key bacteria, including Megasphaera hexanoica, to reside within the lung tumour microenvironment and produce enzymes involved in anaerobic glycolysis.

Background

The ability of tumour cells to rapidly grow and proliferate is often limited by increasing energy demands. Counteracting mechanisms are thought to exist to evade such limitations however, and include angiogenesis as well as intracellular metabolic reprogramming1, both recognised within the hallmarks of cancer2. Referred to as the ‘Warburg effect’, deregulated intratumoural metabolism involves increased uptake of glucose and preferential production of lactate through glycolytic pathways, even in the presence of oxygen3. Such a mechanism allows tumour cells to survive and proliferate even in anaerobic conditions.

This ability draws parallels to that of bacteria, some of which have similarly evolved to survive in anaerobic environments. There is growing evidence to suggest the presence of intratumoural bacteria, that are unique to the tumour microenvironment and distinct to surrounding tissue of the same organ type.

Given the evolutionary capabilities of bacteria to survive in anaerobic environments, we hypothesise that intratumoural bacteria may play a functional role in the Warburg effect and the shift towards glycolytic metabolism in patients with lung cancer.

Methods

We leveraged BioCorteX’s industry leading knowledge graph and integrated proprietary technology engines. Utilising a data driven mechanistic approach, over 8,000 lung tumour microbiome samples were analysed in BioCorteX’s Carbon MirrorTM platform v20230504_112227. Specifically, bacterial species were investigated capable of producing a set of glycolytic enzymes of interest, including lactate dehydrogenase.

Results

14.6% of distinct intratumoural bacterial species residing within lung tumour samples were found to produce at least one glycolytic enzyme contributing to the Warburg effect. These bacteria comprised 66.7% of the total abundance of bacterial species across all lung tumour samples investigated. In-depth analysis revealed several organisms, including Megasphaera hexanoica, to contain all enzymes of interest within the glycolytic pathway.

Conclusion

Our findings suggest that intratumoural bacteria in lung cancer may contribute to the Warburg effect through the production of glycolytic enzymes. Using a data-led mechanistic approach, we have independently identified Megasphaera hexanoica to contribute via this mechanism, a bacterial species that has previously been proposed as a biomarker for lung cancer5. This work supports the emerging view that intratumoural bacteria may play a functional rather than a bystander role in the tumour microenvironment.

References

1. Warburg, O. On the origin of cancer cells. Science 123, 309–314 (1956).
2. Hanahan, D. & Weinberg, R. A. Hallmarks of Cancer: The Next Generation. Cell 144, 646–674 (2011).
3. Pavlova, N. N. & Thompson, C. B. THE EMERGING HALLMARKS OF CANCER METABOLISM. Cell Metab. 23, 27–47 (2016).
4. Nejman, D. et al. The human tumor microbiome is composed of tumor type-specific intracellular bacteria. Science 368, 973–980 (2020).
5. Lee, S. H. et al. Characterization of microbiome in bronchoalveolar lavage fluid of patients with lung cancer comparing with benign mass like lesions. Lung Cancer 102, 89–95 (2016).