Origin and adaptation of Fusobacterium nucleatum during colonisation of the human colorectal cancer microenvironment

• Applicant: Dr. Felix Michael Key
• Subject Area: Medical Microbiology and Mycology, Hygiene, Molecular Infection Biology ; General Genetics and Functional Genome Biology ; Hematology, Oncology ; Metabolism, Biochemistry and Genetics of Microorganisms
• Term: from 2018 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 405554765

Cancer remains a major health-care burden, and understanding the role of bacteria during cancer development can open up new avenues in clinical care. Colorectal cancer (CRC) is a leading cause of death and linked to mutations in particular oncogenes. Interestingly, CRC is strongly and reproducibly associated with Fusobacterium nucleatum, which is the most abundant bacterial species in the tumour microenvironment and may play a role in initial colorectal tumorigenesis. However, F. nucleatum is commensal in the oral cavity and rarely detected in the gut microbiome of healthy individuals. F. nucleatum recovered from inflamed gut tissue are more invasive than those from healthy tissue, pointing to a phenotype that might facilitate tumorigenesis. Although, association of F. nucleatum is evident already with early stage colorectal neoplasia, the exact timing of gut colonisation in relation to cancer development is unknown. Importantly, it is not understood if pre-existing strain-level variants, adaptive de novo mutations occurring within a person, or both facilitate its translocation and successful establishment in the gut environment. To elucidate the origin and adaptation of F. nucleatum at the tumour microenvironment we will culture and sequence hundreds of F. nucleatum isolates harvested from dozens of human colon biopsies (incl. CRC) and saliva. The recovered genetic diversity of F. nucleatum strains within individual people will allow me to infer their intra-host evolutionary history. Specifically, I will leverage the genetic variation of F. nucleatum within individual people to reconstruct the phylogenetic relationship and infer the timing and translocation patterns of F. nucleatum. Further, I will assess signatures of adaptation in F. nucleatum to the tumour microenvironment and other habitats within individuals by analysing parallel mutations across genes and functional pathways. Lastly, I will test if the presence of F. nucleatum in the tumour microenvironment is associated with CRC-specific mutated oncogenes. Taken together, through the proposed research project we will understand the source of F. nucleatum at the tumour microenvironment, the driver mutations responsible for successful colonisation, and possibly a causal relationship between F. nucleatum and CRC. Thereby, this project has the power to elucidate new targets for prevention, diagnosis as well as for probiotic and antibiotic therapy of CRC. Overall, it will improve our understanding of the complex dynamic interplay of human microbiota with disease.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professorin Tami D. Lieberman, Ph.D.