Mapping Tumor-Infiltrating Microbes: Microniches to Single Cells in the Tumor Microenvironment

Within human gastrointestinal tract tumors, malignant cells are surrounded by a complex ecosystem that includes a range of non-transformed human cells, as well as a diverse collection of microorganisms. The goal of my research program is to understand the impact of tumor-infiltrating bacteria on cancer progression and patient response to treatment. My talk will begin by discussing our findings that specific tumor-infiltrating bacteria are an intrinsic component of the colorectal cancer tumor microenvironment, persisting with the cancer even at distant metastatic sites (Bullman et al., Science, 2017).

Additionally, I will highlight our serendipitous findings during the search for a small molecule inhibitor of the oncomicrobe Fusobacterium nucleatum (sensu lato), which revealed a complex interplay between the intratumoral microbiota and cancer treatment drugs (LaCourse et al., Cell Reports, 2022). I will also present our recent efforts to understand the contribution of the intratumoral microbiota to the tumor microenvironment (Galeano Nino et al., Nature, 2022). Specifically, we sought to determine where these microbes physically reside within tumor tissue, what host cells they are interacting with, and most importantly, the consequences of these interactions. To do this, we adapted and applied emerging technologies, including spatial transcriptomics, spatial proteomics, and single-cell sequencing (developed as INVADEseq, Galeano Nino et al., Nature Protocols, 2023), to profile host-microbial interactions in human oral and colorectal cancers. Our results reveal that the intratumoral microbiota is not randomly distributed within human oral and colorectal tumors but instead are localized to distinct microniches associated with immune and epithelial cell functions that support cancer progression.

Finally, I will discuss our recent pangenomic and functional studies on Fusobacterium strains isolated from human colorectal cancer tumors, revealing a distinct Fusobacterium nucleatum (sensu lato) clade that dominates the human colorectal cancer tumor niche (Zepeda-Rivera et al., Nature, 2024). Understanding how the microbiota impacts cancer progression and patient responses to treatment will facilitate the development of novel therapeutic approaches that incorporate the microbial component of the tumor microenvironment.