In a recent article published in the journal Immunity, the authors discussed the findings from a 2022 study by Galeano Niño et al., which reported that microbiota associated with tumors form micro-niches and play a role in epithelial and immune mediations of cancer.
Study: Putting bacteria on the cancer map. Image Credit: Volodimir Zozulinskyi / Shutterstock
Background
A growing body of evidence indicates that microbiomes play significant roles in health and disease. Although cancers are considered genetic in origin, studies suggest that microbial associations play an important role in the microenvironment of the tumors and the dissemination and proliferation of cancers. However, the molecular mechanisms of the microbiota in modulating tumor microenvironments and their role in sensitivity to immunotherapies or other cancer therapies remain unclear.
The development of sequence-based analyses and computational tools, combined with the traditional flow cytometry and microscopy methods, have provided an opportunity to study the microbial interactions with host cells in various types of cancers. While studies have found that the diversity of microbiomes varies with different types of cancer, the microorganisms associated with specific tumors and their roles in the tumor microenvironment were not well understood. Galeano Niño et al. used single-cell ribonucleic acid sequencing (scRNA-seq), bulk sequencing, and spatial imaging technology to address these aspects.
Major findings
The study by Galeano Niño et al. found that microbiomes were distributed in specific cellular compartments, which could be associated with distinct roles in tumorigenesis. Their analysis of 16S RNA sequences of tissue samples obtained from 11 colorectal cancer patients revealed that tumors had varying associations with microorganisms, and colon cancers had a recognized association with Fusobacterium nucleatum.
Furthermore, a spatial transcriptomics platform was used to understand the identity and distribution of intratumoral microbiota in colorectal cancer and oral squamous cell carcinoma tumors. Microbial ribosomal RNA (rRNA) transcripts, which are generally discarded during the analysis of human scRNA-seq data, were used to quantify the transcriptional loads of individual microorganisms. This method successfully identified the bacterial transcripts in 46% and 28% of colorectal cancer and oral squamous cell carcinoma tumor capture sites, respectively. These results suggested a non-random association of microbiota within niches in the tumors.
Additionally, 77 cancer progression and anti-tumor immunity-related proteins were used in a proteomic approach to understand the spatial distribution of microbiota within tumors. For this analysis, the researchers selected immune and epithelial tumor compartments. The bacteria in the immune compartments were found in highly immunosuppressive micro-niches with low T cell levels and mature myeloid cells. This suggested that tumor regions containing bacteria suppress the recruitment and function of T cells and recruit myeloid populations.
In comparison to regions without bacteria, bacteria-positive regions in the epithelial compartment were associated with lower levels of tumor protein p53 and lower vascularization, along with increased mitogen-activated protein kinase signaling and decreased proliferation. In contrast to what was understood about angiogenesis in cancers, these results suggested a decrease in vascularization.
Galeano Niño et al. also developed a method called invasion-adhesion-directed expression sequencing or INVADEseq to determine associations between bacterial and specific host cell types. This method allows the 16S rRNA of the bacteria and human RNA from a single cell to be sequenced concurrently, which is useful in documenting the microorganisms associated with individual cancer cells. INVADEseq was used to identify infected cells and profile the human and bacterial RNA transcriptomes from three colorectal cancer cell lines and seven oral squamous cell carcinoma patients.
The INVADEseq technology could also be used to compare transcriptomes between the same cancer cell type with and without bacteria. The results showed that cells with microbes had a higher expression of signaling pathways associated with metastasis, deoxyribonucleic acid (DNA) repair, cancer cell invasion, and dormancy.
Additionally, the culturing of colorectal cancer spheroids with and without colorectal cancer isolates of F. nucleatum revealed that when embedded in neutrophil-containing collagen matrices, the neutrophils formed clusters within the spheroids when F. nucleatum was present, while in the absence of the bacteria, they moved freely. Combined with the findings that bacteria-positive niches recruit myeloid cells, these results show that microbiomes associated with tumors increase cancer cells' ability to metastasize.
Conclusions
Overall, the results from the study by Galeano Niño et al. indicated that tumors contain specific microbial immunosuppressive niches that recruit myeloid cells and decrease T-cell function. The findings also broadly indicate that microbiomes might play varying roles throughout the neoplastic process. Furthermore, the microbial niches associated with the recruitment of myeloid cells could be potential therapeutic targets for cancer treatment.
Journal references:
- Anderson, N. D., & Behjati, S. (2023). Putting bacteria on the cancer map. Immunity, 56(1), 11–13. https://doi.org/10.1016/j.immuni.2022.12.016
- Galeano Niño, J. L., Wu, H., LaCourse, K. D., Kempchinsky, A. G., Baryiames, A., Barber, B., Futran, N., Houlton, J., Sather, C., Sicinska, E., Taylor, A., Minot, S. S., Johnston, C. D., & Bullman, S. (2022a). Effect of the intratumoral microbiota on spatial and cellular heterogeneity in cancer. Nature, 1–8. https://doi.org/10.1038/s41586-022-05435-0
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