Systematic identification of drivers controlling Fusobacterium and oral squamous cell carcinoma interactions

PROJECT SUMMARY A growing body of literature suggests that a large subset of tumors, especially those along the digestive tract, are colonized by bacteria, with one of the most well-documented intratumoral bacteria being Fusobacterium nucleatum (Fn). Despite being a normal member of the oral cavity microbiome, Fn has been found in oral squa- mous cell carcinomas, esophagogastric cancers, and colorectal cancers. In a manuscript currently under review, we demonstrate that the total burden of bacteria within a tumor, which strongly correlates with intratumoral Fn levels, is linked to an immunosuppressive microenvironment and resistance to immune checkpoint blockade. However, it remains unknown why only some tumors accumulate bacteria, and why only some bacteria such as Fn become enriched within tumors. In preliminary studies in head and neck squamous cell carcinomas (HNSCC), we found that tumor cell lines exhibited distinct responses to co-culture with Fn, and that Fn strains exhibit widely varying levels of invasiveness, indicating that there are both tumor and bacteria-intrinsic features that control tumor-Fn interactions and, as a result, tumor severity. To comprehensively identify these features, this study will be the first to integrate functional genomics on both tumor and bacterial cells by bringing together experts in cancer systems biology (Dr. Daniel McGrail) and microbial functional genomics (Dr. Apollo Stacy). In Aim 1, we will identify tumor cell determinants of Fn invasion and altered tumor cell viability. In Aim 2, we will identify microbial determinants of Fn intracellular colonization of tumor cells. Integration of these two novel datasets will provide the foundation to mechanistically understand and therapeutically manipulate interactions between Fn and tumor cells.