Colibactin causes genomic instability and promotes Wnt independence in primary colon epithelial cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE140929 | GEO | 2020/12/03
REPOSITORIES: GEO
Similar Datasets
Project description:We observed that deletion of polyketide synthase (pks) from E. coli NC101 reduces its ability to induce tumors in interleukin-10 knockout (Il10-/-) mice injected with azoxymethane (AOM), without altering histologic inflammation. The goal of this experiment is to assess inflammatory cytokine levels in colonic tissue of these mice. 2 germ-free Il10-/- mice were assayed and used as controls. 3 E. coli NC101 and 3 E. coli NC101-delta-pks monoassociated mice were experimental samples.
2012-07-04 | E-GEOD-39095 | biostudies-arrayexpress
Project description:We observed that deletion of polyketide synthase (pks) from E. coli NC101 reduces its ability to induce tumors in interleukin-10 knockout (Il10-/-) mice injected with azoxymethane (AOM), without altering histologic inflammation. The goal of this experiment is to assess inflammatory cytokine levels in colonic tissue of these mice.
2012-07-04 | GSE39095 | GEO
Project description:We established human colorectal tumor organoids from benign adenoma, primary colorectal cancer or metastasized colorectal cancer. The gene signature of tumor organoids associated with their tumor progression status. We also generated genome-edited organoids from human intestinal organoids recapitulating adenoma-carcinoma sequence. Gene expression signature of the genome engineered organoids were similar to that of adenoma organoids. This result indicated multiple (up to five) genetic mutations were insufficient for gene expression reprogramming of colorectal cancer. We used microarrays to detail the global program of gene expression in human colorectal tumor organoids and artificially mutation introduced organoids.
2015-01-18 | GSE57965 | GEO
Project description:Various species of the intestinal microbiota have been associated with the
development of colorectal cancer (CRC), yet a direct role of bacteria in the
occurrence of oncogenic mutations has not been established. Escherichia coli can
carry the pathogenicity island pks, which encodes a set of enzymes that
synthesize colibactin. This compound alkylates DNA on adenine residues and
induces double strand breaks in cultured cells. Here, we exposed human intestinal
organoids to genotoxic pks+ Escherichia coli by repeated luminal injection over a
period of 5 months. Whole genome sequencing (WGS) of clonal organoids before
and after this exposure reveals a distinct mutational signature, absent from
organoids injected with isogenic pks-mutant bacteria. The same mutational
signature is detected in a subset of 3668 human metastatic cancer genomes,
predominantly in a subset of CRC cases. Our study describes a distinct mutational
signature in CRC and implies that the underlying mutational process directly
results from past exposure to bacteria carrying the colibactin-producing pks
pathogenicity island.
| EGAS00001003934 | EGA
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:Colibactin, a bacterial genotoxin produced by E. coli harboring the pks genomic island, induces cytopathic effects such as DNA breaks, cell cycle arrest and apoptosis. Patients with a colonic dysfunction due to inflammatory bowel disease such as ulcerative colitis have an elevated likelihood of carrying pks+ E. coli in their colon microbiota but it is not clear whether and how they contribute to the pathogenesis of colitis. Using a gnotobiotic mouse model, we show that pks+ E. coli do not affect colonic integrity under homeostatic conditions, with the microbiota remaining separated from the epithelium by a mucus barrier. However, upon chemical disruption of this barrier by DSS, the microbes gain direct access to the epithelium, causing severe epithelial injury, and development of colitis, while mice colonized with an isogenic ΔclbR mutant incapable of producing colibactin suffer significantly less pronounced effects. While ΔclbR-colonized animals show efficient recovery of the mucus barrier and crypt homeostasis, recovery in WT-colonized mice is impaired. Instead, the mucosa remains in a chronic regenerative state characterized by high proliferation and impaired differentiation of enterocytes and goblet cells, preventing the re-establishment of a functional barrier. In turn, pks+ E. coli remain in direct contact with the epithelium, perpetuating the process and triggering chronic mucosal inflammation that morphologically and transcriptionally resembles human ulcerative colitis. It is characterized by high levels of stromal R-spondin 3. Genetic overexpression of R-spondin 3 in colon myofibroblasts is sufficient to mimic this chronic regenerative state, resulting in barrier disruption and expansion of E. coli. Together, our data reveal that pks+ E. coli are pathobionts that upon contact with the epithelium promote severe injury and interfere with recovery, initiating chronic tissue dysfunction and inflammation.
2023-07-10 | GSE205403 | GEO
Project description:Genetic and epigenetic alterations are a fundamental aspect of colorectal cancer formation. There is considerable heterogeneity between colorectal cancers regarding the mutations and methylated genes they carry, and this heterogeneity may arise early in the polyp-cancer sequence. However, our understanding of the epigenetic alterations and gene mutations in colon adenomas and their relation to colorectal cancer is incomplete. Thus, we have assessed the methylome in normal colon mucosa, tubular adenomas, and colorectal adenocarcinomas and have determined the relationship of these findings between adenomas and cancer in the colon. Genome-wide alterations in DNA methylation were found in the normal colon mucosa adjacent to colorectal cancer, tubular adenomas, and colorectal cancer. Three subgroups of CRCs and two subgroups of adenomas were identified on the basis of their DNA methylation patterns. The adenomas separated into a high-frequency methylation class (Adenoma-H) and a low-frequency methylation class. The adenoma-H polyps have a methylated DNA signature similar to non-CIMP CRCs, whereas those of the Adenoma-L class have a similar methylation pattern to normal colon mucosa. The CpGs that account for these signatures are located in intragenic/intergenic regions, which suggests that these two groups of adenomas arise from different stem cell populations. We conducted genome-wide array-based studies and comprehensive data analyses of aberrantly methylated loci in 41 normal colon samples, 42 colon adenomas, and 64 colorectal cancers. Supplementary file 'GSE48684_Matrix_signal_intensities_1.txt.gz': includes the unmethylated and methylated signal intensities from Samples GSM1183439-GSM1183561. Supplementary file 'GSE48684_Matrix_signal_intensities_2.txt.gz': includes the unmethylated and methylated signal intensities from Samples GSM1235135-GSM1235158.
2014-09-08 | E-GEOD-48684 | biostudies-arrayexpress
Project description:We established human colorectal tumor organoids from benign adenoma, primary colorectal cancer or metastasized colorectal cancer. The gene signature of tumor organoids associated with their tumor progression status. We also generated genome-edited organoids from human intestinal organoids recapitulating adenoma-carcinoma sequence. Gene expression signature of the genome engineered organoids were similar to that of adenoma organoids. This result indicated multiple (up to five) genetic mutations were insufficient for gene expression reprogramming of colorectal cancer. We used microarrays to detail the global program of gene expression in human colorectal tumor organoids and artificially mutation introduced organoids. To assess the expression profiling of genome-engineered organoids, we prepared total-RNA from cultured adenoma, carcinoma and genome-engineered organoids. We produced two types of genome-engineered organoids using the CRISPR/Cas9 or lentivirus vector system. Each engineered gene and engineered methods are described as a single alphabet and method name, respectively, in the sample characteristics field. The abbreviations for the engineered genes are as follows. 1) Genome-engineered organoids with CRISPR/Cas9 A = APC deletion; K = KRAS G12V knock in; S = Smad4 deletion; T = TP53 deletion; P = PIK3CA E545K knock in. 2) Genome-engineered organoids with Lent virus vector B = CTNNB1 S33Y overexpression; K = KRAS G12V overexpression; S = Smad4 shRNA overexpression; T = TP53 shRNA overexpression; P = PIK3CA E545K overexpression.
2015-01-18 | E-GEOD-57965 | biostudies-arrayexpress
Project description:Genetic and epigenetic alterations are a fundamental aspect of colorectal cancer formation. There is considerable heterogeneity between colorectal cancers regarding the mutations and methylated genes they carry, and this heterogeneity may arise early in the polyp-cancer sequence. However, our understanding of the epigenetic alterations and gene mutations in colon adenomas and their relation to colorectal cancer is incomplete. Thus, we have assessed the methylome in normal colon mucosa, tubular adenomas, and colorectal adenocarcinomas and have determined the relationship of these findings between adenomas and cancer in the colon. Genome-wide alterations in DNA methylation were found in the normal colon mucosa adjacent to colorectal cancer, tubular adenomas, and colorectal cancer. Three subgroups of CRCs and two subgroups of adenomas were identified on the basis of their DNA methylation patterns. The adenomas separated into a high-frequency methylation class (Adenoma-H) and a low-frequency methylation class. The adenoma-H polyps have a methylated DNA signature similar to non-CIMP CRCs, whereas those of the Adenoma-L class have a similar methylation pattern to normal colon mucosa. The CpGs that account for these signatures are located in intragenic/intergenic regions, which suggests that these two groups of adenomas arise from different stem cell populations.
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Project description:We report the RNA-seq data of 40 advanced colorectal adenoma patients form Dongguk University Ilsan International Hospital. The polyps with a diameter of 1cm or greater were regarded as advenced colorectal adenoma and obtained through colonoscopy. The data consist of 22 tublar adenoma, 6 tublovillous adenoma, 5 sessile serrated adenoma/polyp, 1 traditional serrated adenoma, intramucosal adenocarcinoma, neuroendocrine tumor, hyperplastic polyp, inflammatory polyp, high grade dysplasia, and atypical glands with adjacent hyperplastic mucosa.
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