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Bacteroides fragilis toxin promotes gallbladder cancer in mice

ABSTRACT: Enterotoxigenic Bacteroides fragilis (ETBF), which secretes B. fragilis toxin (BFT) and has been associated with colorectal cancer, can be enriched in patients with gallbladder cancer (GBC). Whether and how ETBF contributes to GBC is unclear. Here we confirm using analysis of patient samples that ETBF is enriched in GBC tumors, while experiments in mice show that ETBF colonises the gallbladder. In vitro, and in patient-derived organoids, ETBF promoted GBC proliferation. ETBF also promoted tumor growth in a BFT-dependent manner in a mouse GBC allograft model. Mechanistically, the tumorigenic activity of BFT was dependent upon the ETBF surface protein, MltD, which interacts with the host receptor protein, TMPRSS13. This interaction activated JAK2-STAT3 signaling to promote tumorigenesis. BFT also activated NF-κB signaling, which increased CXCL1 secretion, leading to myeloid-derived suppressor cells recruitment and angiogenesis in the tumor microenvironment. Taken together, these findings uncover mechanisms through which ETBF facilitates GBC development, with potential promise as therapeutic targets to limit GBC progression.

ORGANISM(S): Homo Sapiens

SUBMITTER: Wenguang Wu

PROVIDER: PXD078162 | iProX | Thu May 07 00:00:00 GMT+01:00 2026

REPOSITORIES: iProX

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Project description:Genomic and epigenomic studies support that adenocarcinomas of the gallbladder develop according to a metaplasia-biliary intraepithelial neoplasia (BilIN)-adenocarcinoma histogenic sequence, in which metaplasia and BilIN are non-cancerous lesions of the epithelium. Moreover, recent genomic data suggest that adenocarcinoma can develop in a BilIN-dependent or -independent way, pointing toward patient-specific tumourigenic processes. Spatial transcriptomic data addressing these processes are still missing. Here, using GeoMx digital spatial profiling (NanoString), we characterized the spatial transcriptome of normal gallbladder epithelium, BilINs and adenocarcinoma coexisting within the same samples. To address intra-patient variability we profiled the whole transcriptome of a high number of regions of interest (ROIs) per sample in two patients (Patient #1, 81 year old woman: 24 ROIs; Patient #2, 53-year old man:32 ROIs), with each ROI covering approximately 200 cells of normal epithelium, low-grade BilIN, high-grade BilIN or adenocarcinoma. Our results showed that each type of lesion displayed little transcriptomic variability within the same patient, but differed significantly between patients. They also suggested that adenocarcinoma can derive from high-grade BilIN or from low-grade BilIN, with co-existing high-grade BilIN evolving via a distinct process in the latter case. We also provide strong evidence for patient-specific tumourigenic mechanisms, characterized by distinct sequences of signalling pathway activation. Among those pathways, we functionally investigated SEMAPHORIN 4A (SEMA4A) and provided evidence that repression of SEMA4A expression, as is observed in the gallbladder samples of the two patients, can enhance cell migration and survival, and perturb polarisation of the epithelial cells. In conclusion, our results support that gallbladder adenocarcinoma develops according to patient-specific processes that can be promoted by repression of SEMA4A. They underscore the need to gain gene expression data in addition to histological information to evaluate the risk of low-grade preneoplastic lesions.

Project description:The cellular heterogeneity of one patient derived orthotopic breast cancer xenograft model (PDBCX) was investigated using flow cytometry , combined with assessment of in vivo tumorigenicity and whole genome expression profiling. Epithelial cell adhesion molecule (EpCAM) was revealed as a highly specific cell surface marker of the human tumor cell population in both xenografts. Based on expression patterns observed in primary tumor tissue, SSEA-4 and CD24 were chosen as markers to further subdivide the luminal tumor cells into four subpopulations. FACS sorting was used to isolate four cell subpopulations. Results: In vivo tumorigenicity assay showed that SSEA-4+/CD24+ cells were non-tumorigenic, while the three other subpopulations were tumorigenic. Tumors resulting from the SSEA-4+/CD24- subpopulation of luminal cancer cells, did not express CD24, while tumors arising from the SSEA-4-/CD24-, and SSEA-4-/CD24+ populations both recapitulated the original tumor containing all four subpopulations. Whole genome expression analysis revealed distinct transcriptional profiles, and 44 genes were significantly differentially expressed when comparing the tumorigenic vs non-tumorigenic populations. Several interesting genes putatively suppressing the cancer cells ability to initiate tumors in vivo were upregulated in the non-tumorigenic population. We here show that tumor initiating cells within one primary tumor evidently included more than one phenotype. Furthermore, with respect to cell surface marker expression, one of the subpopulations produced tumors unlike both the originating cells, and the original tumor. Discussion: Our results imply that subpopulations from one primary tumor can give rise to dissimilar daughter tumors. These tumors may not necessarily respond to the same targeted treatment, and thereby represent a therapy escape mechanism. This study highlights that to remove the risk of breast cancer recurrence, inhibition of the molecules critical for driving the tumor progression in several tumor cell subpopulations might be essential Gene expression was measured in four cell subpopulations isolated from Patient derived human luminal-like breast cancer xenograft. Four replicates from three subpopulations and three replicates from one subpopulation.

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Bacteroides fragilis toxin promotes gallbladder cancer in mice

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