Colibactin action in mouse colon epithelial cells
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB35529 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR3684840_1.fastq.gz | Fastqsanger.gz | |||
| ERR3684840_2.fastq.gz | Fastqsanger.gz | |||
| ERR3684850_1.fastq.gz | Fastqsanger.gz | |||
| ERR3684850_2.fastq.gz | Fastqsanger.gz | |||
| ERR3684860_1.fastq.gz | Fastqsanger.gz |
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Project description:Colibactin causes genomic instability and promotes Wnt independence in primary colon epithelial cells
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Project description:Various bacteria are suggested to contribute to colorectal cancer (CRC) development, including pks+ E. coli, which produces the genotoxin colibactin that induces characteristic mutational signatures in host epithelial cells. However, it remains unclear how the highly unstable colibactin molecule is able to access host epithelial cells to cause harm. Using the microbiota-dependent ZEB2-transgenic mouse model of invasive CRC, we demonstrate that the oncogenic potential of pks+ E. coli critically depends on bacterial adhesion to host epithelial cells, mediated by the type-1 pilus adhesin FimH and the F9-pilus adhesin FmlH. Blocking bacterial adhesion using a pharmacological FimH inhibitor attenuates colibactin-mediated genotoxicity and CRC exacerbation. We also show that allelic switching of FimH strongly influences genotoxic potential of pks+ E. coli and can induce a genotoxic gain-of-function in the probiotic strain Nissle 1917. Adhesin-mediated epithelial binding subsequently allows the production of the genotoxin colibactin in close proximity to host epithelial cells, which promotes DNA damage and drives CRC development. These findings present promising therapeutic avenues for the development of anti-adhesive therapies aimed at mitigating colibactin-induced DNA damage and inhibiting the initiation and progression of CRC, particularly in individuals at risk for developing CRC.
2024-08-19 | GSE241851 | GEO
Project description:Colorectal cancer is driven by a sequential cascade of mutations known as the adenoma-carcinoma sequence. Recent studies have revealed that specific bacterial species present in the colonic microbiota can induce mutations and contribute to this malignancy. Specifically, genotoxic colibactin-producing pks+ Escherichia coli strains can induce DNA double strand breaks (DSBs) and promote tumor development in mouse models of colorectal cancer. Here, we investigated the transformation potential of colibactin by using organoids and polarized monolayers derived from primary murine colon epithelial cells and reveal striking phenotypic changes upon short-term infection. This study demonstrates the direct pro-oncogenic potential of pks+ E. coli, as such transformations in vivo could facilitate colitis-associated colorectal carcinogenesis.
2020-12-03 | GSE140929 | GEO
Project description:Colibactin-driven colon cancer requires adhesin-mediated epithelial binding
| PRJNA1010330 | ENA
Project description:Colibactin, a potent genotoxin of Escherichia coli, causes DNA double strand breaks (DSBs). We investigated if colibactin creates a particular DNA damage signature in infected human cells. Genomic contexts of colibactin-induced DSBs were enriched for a distinct AT-rich hexameric sequence motif. A survey of somatic mutations at the colibactin target sites of several thousand cancer genomes revealed significant enrichment of the motif in colorectal cancers. Moreover, the exact break point location corresponded with mutational hot spots in these cancers corresponding to a distinct trinucleotide signature. This work provides evidence for a role of colibactin in the etiology of human cancer.
2020-04-22 | GSE145594 | GEO
Project description:By comparing the transcriptome profile upon deletion or overexpression of ClbR or ClbQ, we addressed the role of these proteins in regulation of colibactin expression. Our global screen indicates that ClbR is the key transcriptional activator of colibactin expression. In addition, we further investigated potential transcription start sites of the colibactin determinant.
2020-01-17 | GSE143807 | GEO
Project description:Colibactin is a secondary metabolite produced by bacteria present in the human gut and is implicated in the progression of colorectal cancer and inflammatory bowel disease. This genotoxin alkylates deoxyadenosines on opposite strands of host cell DNA to produce DNA interstrand cross-links (ICLs) that block DNA replication. While cells have evolved multiple mechanisms to resolve (“unhook”) ICLs encountered by the replication machinery, little is known about which of these pathways promote resistance to colibactin-induced ICLs. Here, we use Xenopus egg extracts to investigate replication-coupled repair of plasmids engineered to contain site-specific colibactin-ICLs. We show that replication fork stalling at a colibactin-ICL leads to replisome disassembly and activation of the Fanconi anemia ICL repair pathway, which unhooks the colibactin-ICL through nucleolytic incisions. These incisions generate a DNA double-strand break intermediate in one sister chromatid, which can be repaired by homologous recombination, and a monoadduct (“ICL remnant”) in the other. Our data indicate that translesion synthesis past the colibactin-ICL remnant depends on Pol-ita and the Pol-kappa-REV1-Pol-Zitapolymerase complex. Although translesion synthesis past colibactin-induced DNA damage is frequently error-free, it can introduce T>N point mutations that partially recapitulate the mutation signature associated with colibactin exposure in vivo. Taken together, our work provides a molecular framework for understanding how cells tolerate a naturally occurring and clinically relevant ICL.
2025-09-11 | PXD055646 | Pride
Project description:Colon cancer is initiated by stem cells that escape the strict control. In most colon tumors this process is driven through aberrant activation of Wnt signaling by mutations that occur in components acting downstream of the receptor complex and that unfetter tumor cells from the need for Wnt ligands. Here we describe a special type of colon cancer that does not depend on mutated core components of the Wnt pathway. Genetically blocking Wnt secretion from epithelial cells of such tumors results in apoptosis, reduced expression of colon cancer markers, followed by enhanced tumor differentiation. In contrast to the normal colonic epithelium, such tumor cells auto-secrete Wnt ligands to maintain their uncontrolled proliferative behavior. In humans, we determined certain cases of colon cancers in which the Wnt pathway is hyperactive, but not through mutations in its core components. Our findings illuminate the path in therapy to find further subtypes of Wnt- dependent colon cancer, that might be responsive to Wnt secretion inhibitors.
2021-09-01 | GSE181738 | GEO
Project description:The complex reservoir of metabolite-producing bacteria in the gastrointestinal tract contributes tremendously to human health and disease. Bacterial composition, and by extension gut metabolomic composition, is undoubtably influenced by the use of modern antibiotics. Herein, we demonstrate that polymyxin B, a last resort antibiotic used for chronic multidrug resistant infections infections, influences the production of the genotoxic metabolite colibactin from adherent-invasive Escherichia coli (AIEC) NC101. Colibactin can augment colorectal cancer (CRC) through DNA double stranded breaks and interstrand crosslinks. While the structure and biosynthesis of colibactin has been elucidated, chemical-induced regulation of its biosynthetic gene cluster and subsequent production of the genotoxin by pathogenic E. coli are largely unexplored. This research highlights the regulation of the colibactin-producing biosynthetic gene cluster under polymyxin stress. Using a multi-omic approach, we have identified that polymyxin stress enhances the abundance of colibactin biosynthesis proteins (Clb’s) in multiple pks+ E. coli strains, including pro-carcinogenic AIEC: NC101, the probiotic strain: E. coli Nissle 1917, and the antibiotic testing strain: E. coli ATCC 25922. Expression analysis via qPCR revealed that increased transcription of clb genes likely contributes to elevated Clb protein levels in NC101. Enhanced production of Clb’s by NC101 under polymyxin stress matched an increased production of the colibactin prodrug motif, a proxy for the mature genotoxic metabolite. Furthermore, E. coli with heightened tolerance for polymyxin antibiotics induced greater DNA damage, assessed by quantification of γH2AX staining in cultured intestinal epithelial cells. This study establishes a key link between the polymyxin B stress response and colibactin production in pks+ E. coli. Ultimately, our findings will inform future studies investigating colibactin regulation, the microbial response to antibiotics in the gut, and the ability of seemingly innocuous commensal microbes to induce host disease.
2021-07-15 | PXD025088 | Pride
Project description:Gut metagenomes of Mice from NUS Colibactin Project
| PRJEB64247 | ENA