The role of microbiota amino acid metabolism in cancer

Weill Medical Coll Of Cornell Univ, New York NY

Investigators

Abstract

Studies have shown that microbiota composition and their genes and metabolites differ between healthy and cancer patients. However, unraveling their effect on cancer onset or development is challenging due to the lack of an efficient system to manipulate their levels in vivo. Recently, we were able to precisely manipulate microbiota amino acid depletion pathways in vivo and found that some pathways affect host amino acid homeostasis and tumor progression. We hypothesize that the gut bacteria impact the host amino acid homeostasis and affect tumor microenvironment (TME) and progression. Herein, we will identify the microbes (and their genes) that actively deplete intestinal amino acids and evaluate how they affect TME and tumor progression. We will not only learn more about the role of microbiota-mediated amino acid metabolism in cancer progression at the molecular level, our work will also lay the ground for generating a synthetic and engineered gut microbial community with defined metabolic functions to prevent and cure cancer. There are three convergent motivations: First, many microbiota molecular features are different between healthy and cancer patients, and we need functional studies to causally connect them with cancer. We will combine bioinformatics, metabolomics, bacterial genetics, and germ-free and tumor mouse models to modulate microbiome metabolic pathways in the host. This approach will boost a systematic identification of tumor-affecting microbiota genes and pathways; our findings will also promote new therapeutic strategies by targeting these previously unknown microbial metabolic avenues. Second, gut microbiota metabolism significantly impacts host nutrient homeostasis. However, the molecular mechanisms behind how microbiota regulates host amino acid homeostasis and affects tumor progression remain largely unexplored. We believe that this approach can be used to regulate the microbiome metabolic functions at a specific niche to study their effects on cancer. Our finding would also open the door to interrogating – and ultimately controlling – one of the most concrete contributions that gut bacteria make to host biology. Third, a synthetic microbial community with a defined and programmable metabolic function has transformative potential for cancer treatment. The gut microbiome is part of our `pan-genome,' whose metabolic functions are more tractable by genetic manipulation or adjusting microbiota composition. Our approach will expedite the genomic and biological characterization of microbiota metabolic genes, laying the basis for a synthetic community with a defined and programmable metabolic function to prevent and cure cancer.