Effect of the intratumoral microbiota on spatial and cellular heterogeneity in cancer
This is a summary of our Dec 14th, 2022 DalMUG journal club discussion of this paper written by Monica Alvaro Fuss
This study uses in-situ spatial technologies to characterize intratumoral bacteria within the tumour microenvironment of oral squamous cell carcinoma (OSCC) and colorectal cancer (CRC). Their data highlight the bacterial heterogeneity between different tumour types, regions and patients, and focus on the presence of Fusobacterium species. The authors found that bacteria are concentrated within particular microniches, which are characterized by the presence of mature CD66+ myeloid cells, upregulation of immunosuppressive markers including PD-1, and lower densities of CD4+ and CD8+ T cells, in contrast to adjacent bacteria-negative areas. They then describe a novel method for mapping bacterial reads to single human cells, which they used to investigate the role of cell-adherent or intracellular bacteria. They found that mostly macrophages and epithelial cells were bacteria-associated, and that they exhibited upregulation of inflammatory and cancer progression genes, respectively. In epithelial cells, Fusobacterium and Treponema may enhance these signatures beyond a generalized LPS or DAMP response. Finally, culturing CRC epithelial spheroids with F. nucleatum appeared to slow neutrophil migration and promote the detachment and invasion of single infected cancer cells from the spheroid into the collagen matrix. These cells exhibited further upregulation of genes associated with cancer progression and metastasis and downregulation of p53 signalling, cell cycle and DNA damage repair pathways.
Below are the key points that came up during our discussion.
Points of discussion
Small sample sizes for both OSCC and CRC.
The experimental approach used in spatial transcriptomics.
Different taxa were not found to be particularly far apart from each other within the bacterial microniches.
Although somewhat addressed by the authors, we discussed that bacteria found within macrophages would not surprisingly be associated with an inflammatory response
We questioned the detachment of cells from the spheroid as a sign of metastasis instead of regular cell death as a result of co-culturing with bacteria. However, the use of a collagen matrix as well as the metastatic and EMT-related transcriptomic profiles appears to support the author’s view.
We agreed that this study shows interesting evidence of the cancer-promoting role of intratumoral microbiota, but that further investigation is required to tease out the ‘chicken-or-the-egg’ problem that currently underlies the role of bacteria in immunosuppression, inflammation and progression within the tumour microenvironment.