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Improved detection of colibactin-induced mutations by genotoxic E. coli in organoids and colorectal cancer
Open accessAbstract
Co-culture of intestinal organoids with a colibactin-producing pks + E. coli strain (EcC) revealed mutational signatures also found in colorectal cancer (CRC). E. coli Nissle 1917 (EcN) remains a commonly used probiotic, despite harboring the pks operon and inducing double strand DNA breaks. We determine the mutagenicity of EcN and three CRC-derived pks + E. coli strains with an analytical framework based on sequence characteristic of colibactin-induced mutations. All strains, including EcN, display varying levels of mutagenic activity. Furthermore, a machine learning approach attributing individual mutations to colibactin reveals that patients with colibactin-induced mutations are diagnosed at a younger age and that colibactin can induce a specific APC mutation. These approaches allow the sensitive detection of colibactin-induced mutations in ∼12% of CRC genomes and even in whole exome sequencing data, representing a crucial step toward pinpointing the mutagenic activity of distinct pks + E. coli strains.
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“having the capability of synthetizing and releasing colibactin, a mutagenic substance described to promote colorectal polyposis and cancer, and reducing cancer response to irinotecan [26, 34–39].”
From Selection, Comparative Genomics, and Potential Probiotic Features of Escherichia coli 5C, a pks-Negative Strain Isolated from Healthy Infant Donor Feces (2026) · cites this paper as [39]
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“Indeed, pks-positive CRC occurs mainly in young people [39].”
From Selection, Comparative Genomics, and Potential Probiotic Features of Escherichia coli 5C, a pks-Negative Strain Isolated from Healthy Infant Donor Feces (2026) · cites this paper as [39]
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“the pks genetic island is absent in the E. coli 5C but present and productive in the E. coli Nissle 1917 [39].”
From Selection, Comparative Genomics, and Potential Probiotic Features of Escherichia coli 5C, a pks-Negative Strain Isolated from Healthy Infant Donor Feces (2026) · cites this paper as [39]
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“the most widely used E. coli-based probiotic, known as E. coli Nissle 1917 (DSM 6601), is pks-positive.”
From Selection, Comparative Genomics, and Potential Probiotic Features of Escherichia coli 5C, a pks-Negative Strain Isolated from Healthy Infant Donor Feces (2026) · cites this paper as [39]
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Metadata
- Authors
- Rosendahl Huber, A., Pleguezuelos-Manzano, C., Puschhof, J., Ubels, J., Boot, C., Saftien, A., Verheul, M., Trabut, L. T., Groenen, N., van Roosmalen, M., Ouyang, K. S., Wood, H., Quirke, P., Meijer, G., Cuppen, E., Clevers, H., & van Boxtel, R.
- Affiliations
- Royal Netherlands Academy of Arts and Sciences (NL)
- Oncode Institute (NL)
- German Cancer Research Center (DE)
- University of Leeds (GB)
- The Netherlands Cancer Institute (NL)
- University Medical Center Utrecht (NL)
- F. Hoffmann-La Roche AG (CH)
- Corresponding author
- Puschhof, Jens
- Clevers, Hans
- ORCID
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2024-03
- Volume
- 42
- Issue
- 3
- Pages
- 487-496.e6
- ISSN
- 1535-6108 (ISSN-L)
- OpenAlex
- W4392638507
- Cited by
- 106
- References
- 52
- Citations by year
- 2026: 53 · 2025: 39 · 2024: 14
- FWCI
- 32.02
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion, cc-by)
- PubMed (publishedVersion)
- KNAW Research Portal (The Royal Netherlands Academy of Arts and Sciences) (publishedVersion, other-oa)
- White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion, cc-by)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- Funders
- American Association for Cancer Research (SU2C-3.1416)
- European Research Council (864499)
- Hubrecht Institute
- Cancer Research UK (C10674/A27140)
- Ministerie van Onderwijs, Cultuur en Wetenschap
- National Human Genome Research Institute
- Entertainment Industry Foundation
- Oncode Institute
- National Cancer Institute
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek
- New York Stem Cell Foundation
- Princess Máxima Center for Pediatric Oncology
- KWF Kankerbestrijding
- Koninklijke Nederlandse Akademie van Wetenschappen
- Energy Council of Canada (2F8, CFF16-2F8, CFF159-19H2, 19H2)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Carcinogens and Genotoxicity Assessment
- Keywords
- colibactin, Escherichia coli, colorectal cancer, intestinal organoids, mutagenicity, genotoxicity, Escherichia coli Nissle 1917, probiotics, DNA double-strand breaks, APC mutation, mutational signatures, age at diagnosis
- MeSH terms
- DNA Damage, Escherichia coli, Humans, Mutagens, Mutation, Organoids, Peptides, Colorectal Neoplasms, Polyketides
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