Modulation of the tumor microenvironment by Fusobacterium nucleatum and co-infecting microbes in colorectal cancer

/ABSTRACT Fusobacterium nucleatum (Fn), a bacterium typically found in the human oral cavity and a rare member of the lower gastrointestinal tract microbiota in healthy individuals, is significantly enriched in human colorectal cancer (CRC) tissues. Extensive epidemiological studies have established a strong association between high Fn levels within CRC tumors and disease recurrence, metastasis, and poor patient prognosis. However, Fn does not exist alone within these tumors; it coexists with a specific group of anaerobic bacterial species. Our previous work demonstrated the persistence of both Fn and these co-infecting bacteria in distant metastases of CRC patients and in CRC patient-derived xenografts (PDXs). Additionally, antibiotic treatment of PDXs effectively reduced intratumoral microbial load and slowed tumor growth, emphasizing the integral role of Fn and co-infecting bacterial communities within the CRC tumor microenvironment (TME). Despite these findings, the field of cancer microbiome research has predominantly focused on bulk tissue molecular analysis, resulting in a fundamental gap in our understanding of the spatial and cellular interactions between Fn, co-infecting bacteria, and human components within the TME. Recent discoveries by my team have revealed that Fn and co-infecting bacteria exhibit a heterogeneous distribution within human CRC tumors, localized to distinct tumor niches. These infected regions are characterized by myeloid cell infiltration, upregulation of immune checkpoint proteins PD1 and CTLA4, and reduced T-cell infiltration. Our central hypothesis posits that Fn and specific co-infecting bacteria collectively reshape their infected CRC tumor niche by influencing cancer epithelial cell functions and the spatial distribution of immune cells in infected regions; ultimately driving cancer progression. To test this hypothesis, we will leverage cutting-edge spatial omics techniques to investigate how the composition, load, and spatial distribution of Fn and co-infecting bacteria affect the function and spatial organization of host cellular components within the TME of both human and murine CRC tumors (Aim 1). Furthermore, we will dissect host-bacterial interactions at the single-cell level to reveal specific host cell types susceptible to invasion by Fn and co-infecting bacteria within the CRC TME and determine how these intracellular bacteria alter host signaling pathways at the single-cell level (Aim 2). My team has the breadth of experience to accomplish this project as it relates to the multiomics nature of analyses for Fn, co-infecting bacteria, and host interactions within the CRC TME. Successful completion of this proposal will bridge a critical knowledge gap in our understanding of how Fn and co-infecting bacteria shape their infected niche and influence cancer cell behavior in both primary and metastatic CRC. This research holds the potential to reveal novel therapeutic targets for inhibiting Fn-associated CRC progression or enhancing existing CRC treatments. While our primary focus is on CRC, the host-microbiota mechanistic insights gained from this study are likely to have broader implications for infection-associated cancers. Project Number: 1R01CA293361-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Susan Bullman | Institution: UNIVERSITY OF TX MD ANDERSON CAN CTR, HOUSTON, TX | Award Amount: $660,541 | Activity Code: R01 | Study Section: Tumor Host Interactions Study Section[THI] View on NIH RePORTER: https://reporter.nih.gov/project-details/11291905