Differences in the on- and off-tumour microbiota between right- and left-sided colorectal cancer

Objective This study aims to determine the differences in the microbial profiles of the on- and off-tumour microbiota between patients with right- and left-sided colorectal cancer.Design Microbial profiling of on- and off-tumour biopsies from patients with right-sided (n=17) and left-sided (n=7) colorectal adenocarcinoma was performed using 16S ribosomal RNA sequencing. Results Off-tumour alpha diversity is significantly greater in right-sided compared to left-sided colorectal cancer patients. However, no differences in on-tumour alpha diversity were observed between tumour locations. Off-tumour beta diversity showed distinctive bacterial community clusters between the right and left colon, while no significant differences in beta diversity were observed in the on-tumour microbiota. The off-tumour microbiota showed the right colon to be enriched with species of the Lachnoclostridium, Selenomonas and Ruminococcus genera, whereas the left colon is enriched with Epsilonbacteraeota phylum, Campylobacteria class, and Pasteurellales and Campylobacterales orders. In contrast the on-tumour microbiota showed relatively fewer differences in bacterial taxonomy between tumour sites, with left tumours being enriched with Methylophilaceae and Vadin BE97 families and Alloprevotella, Intestinibacter, Romboutsia and Ruminococcus 2 genera. Comparison of paired on- and off-tumour microbiotas showed that patients with left-sided colorectal cancer had large taxonomic differences between their on- and off-tumour microbiota, while patients with right-sided colorectal cancer showed relatively fewer taxonomic differences.Conclusion The off-tumour microbiota is more diverse in the right compared to the left colon, showing distinct community clusters and large differences in bacterial taxonomy. In contrast the on-tumour microbiota shows no difference in bacterial diversity and relatively fewer differences in bacterial taxonomy. Collectively this suggests that the right and left colon show distinctive bacterial communities, however, the presence of a colonic tumour leads to a more consistent microbiota between locations. Trial registration number clinicaltrials.gov (NCT01701310).

Stromal Hedgehog signalling is downregulated in colon cancer and its restoration restrains tumour growth

A role for Hedgehog (Hh) signalling in the development of colorectal cancer (CRC) has been proposed. In CRC and other solid tumours, Hh ligands are upregulated; however, a specific Hh antagonist provided no benefit in a clinical trial. Here we use Hh reporter mice to show that downstream Hh activity is unexpectedly diminished in a mouse model of colitis-associated colon cancer, and that downstream Hh signalling is restricted to the stroma. Functionally, stroma-specific Hh activation in mice markedly reduces the tumour load and blocks progression of advanced neoplasms, partly via the modulation of BMP signalling and restriction of the colonic stem cell signature. By contrast, attenuated Hh signalling accelerates colonic tumourigenesis. In human CRC, downstream Hh activity is similarly reduced and canonical Hh signalling remains predominantly paracrine. Our results suggest that diminished downstream Hh signalling enhances CRC development, and that stromal Hh activation can act as a colonic tumour suppressor.