Abstract
Intratumoral microbiota are organized into microniches that alter immune and epithelial cell function.
Major Finding: Intratumoral microbiota are organized into microniches that alter immune and epithelial cell function.
Concept: Bacteria–host cell interactions affect pathways involved in inflammation, DNA repair, and tumor progression.
Impact: These highly organized bacterial-positive microniches promote cancer heterogeneity and progression.
Tumor-associated microbiota play a critical role in cancer development, metastasis, immunosurveillance, and chemoresistance across a wide variety of tumor types. To date, most studies that have investigated intratumoral host–microbiota interactions have relied on bulk tissue analysis, which inhibits the evaluation of spatial distribution of the microbiota within tumors. To reveal the spatial, cellular, and molecular host–microbe interactions present in cancer, Galeano Niño and colleagues conducted in situ spatial profiling and single-cell RNA sequencing in oral squamous cell carcinoma (OSCC) and colorectal cancer (CRC), which showed that the distribution of intratumoral microbiota varies within individual patient tumors. Spatial distribution indicated both densely populated and bacteria-negative regions, with additional studies revealing that bacteria reside in highly immunosuppressive microniches that are characterized by myeloid cell infiltration and T-cell exclusion that are less vascularized and have decreased malignant cell proliferation. To further investigate bacterial–host cell-to-cell interactions in the tumor microenvironment, the single-cell RNA sequencing method INVADEseq (invasion-adhesion-directed expression sequencing) was developed, and its application demonstrated that the major intracellular bacterial species in OSCC were from the Fusobacterium and Treponema genera, with these species being predominately associated with aneuploid epithelial and monocyte-derived macrophage cells. Moreover, the presence of these bacteria led to the significant upregulation of gene expression and signaling pathways related to cancer progression, suggesting that specific cell-associated bacteria can affect single-cell intratumoral heterogeneity. Assessment of the direct interaction between the intratumoral microbiota with immune and tumor cells indicated that neutrophil recruitment and retention to CRC tumor spheroid models, cancer cell migration and invasion, and pathways involved in cancer progression, including extracellular matrix remodeling and growth factor signaling, were all enriched by F. nucleatum infection, while F. nucleatum infection also led to alterations in pathways related to cell cycle, dormancy, DNA damage repair, and p53 signaling. In summary, this study demonstrates that intratumoral microbiota contribute to tumor heterogeneity through alterations to distinct cellular compartments as well as changes to antitumor immunity and cancer cell migration, which suggests a critical function for these bacterial-positive microniches in cancer progression.
Note:Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.
RSS Feeds