Bacteroides fragilis Promotes Mesenchymal Subtype in Colorectal Cancer.

Area of Science:

• Oncology
• Microbiology
• Cancer Biology

Background:

• Colorectal cancer (CRC) displays molecular heterogeneity, classified into Consensus Molecular Subtypes (CMS).
• The tumor microenvironment (TME) and microbiome interactions significantly influence CRC progression.
• CMS4, a stromal-rich subtype, is associated with aggressive disease and poor prognosis, yet its microbiome-driven mechanisms are unclear.

Purpose of the Study:

• To investigate the role of the tumor microbiome in shaping the TME and determining CRC subtypes, specifically CMS4.
• To identify microbial species associated with CMS4 tumors.
• To elucidate the functional impact of specific microbes on CMS4 phenotype.

Main Methods:

• Analysis of 25 colorectal cancer tissues using RNA sequencing and CMScaller for subtype classification.
• 16S rRNA profiling to identify significantly enriched microbial species in different CMS subtypes.
• In vitro functional studies using CMS2 organoids co-cultured with stromal and immune cells, exposed to identified microbial species.

Main Results:

• 16S rRNA profiling revealed significant enrichment of Bacteroides fragilis in CMS4 tumors.
• Functional studies demonstrated that enterotoxigenic Bacteroides fragilis (ETBF) exposure induced CMS4-like features in organoids.
• ETBF exposure led to enhanced growth and gene expression patterns mimicking primary CMS4 tumors.

Conclusions:

• Enterotoxigenic Bacteroides fragilis (ETBF) is implicated in the development of the aggressive CMS4 colorectal cancer subtype.
• ETBF may contribute to the acquisition of aggressive phenotypes characteristic of CMS4.
• Targeting ETBF could offer a therapeutic strategy for CMS4 colorectal cancer.