Tolerance to colibactin correlates with homologous recombination proficiency and resistance to irinotecan in colorectal cancer cells
Open accessAbstract
The bacterial genotoxin colibactin promotes colorectal cancer (CRC) tumorigenesis, but systematic assessment of its impact on DNA repair is lacking, and its effect on response to DNA-damaging chemotherapeutics is unknown. We find that CRC cell lines display differential response to colibactin on the basis of homologous recombination (HR) proficiency. Sensitivity to colibactin is induced by inhibition of ATM, which regulates DNA double-strand break repair, and blunted by HR reconstitution. Conversely, CRC cells chronically infected with colibactin develop a tolerant phenotype characterized by restored HR activity. Notably, sensitivity to colibactin correlates with response to irinotecan active metabolite SN38, in both cell lines and patient-derived organoids. Moreover, CRC cells that acquire colibactin tolerance develop cross-resistance to SN38, and a trend toward poorer response to irinotecan is observed in a retrospective cohort of CRCs harboring colibactin genomic island. Our results shed insight into colibactin activity and provide translational evidence on its chemoresistance-promoting role in CRC.
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E. coli Nissle 1917 synthesizes and releases colibactin, a mutagenic substance that promotes colorectal polyposis and cancer and reduces cancer response to irinotecan.
“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 [37]
The Introduction describes colibactin as a genotoxin associated with colorectal cancer and reports increased tumor formation in preclinical mouse models. The Results find that colibactin-tolerant colorectal cancer cells are also resistant to SN38, irinotecan’s active metabolite; the Discussion says clinical resistance remains to be established. These passages do not identify E. coli Nissle 1917 as the producer, establish that it releases colibactin, or show that colibactin itself reduces patients’ response to irinotecan. (LLM, conf=0.87)
Experimental — accuracy not yet measuredE. coli Nissle 1917 is pks-positive.
“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 [37]
The Introduction says that some E. coli strains harbor the pks island, but does not identify Nissle 1917 as one of them. The References list a paper about the genotoxic activity of Nissle 1917, while the Methods identify a different experimental strain, DH10B pBeloBAC-pks. Searches for Nissle 1917 and DSM 6601 found no passage in our copy stating that Nissle 1917 is pks-positive. (LLM, conf=0.75)
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References 58 · Cited by 17
- Authors
- Sogari, A., Rovera, E., Grasso, G., Mariella, E., Reilly, N. M., Lamba, S., Mauri, G., Durinikova, E., Vitiello, P. P., Lorenzato, A., Avolio, M., Piumatti, E., Bonoldi, E., Aquilano, M. C., Arena, S., Sartore-Bianchi, A., Siena, S., Trusolino, L., Donalisio, M., Russo, M., Di Nicolantonio, F., Lembo, D., & Bardelli, A.
- Affiliations
- IFOM (IT)
- University of Turin (IT)
- Candiolo Cancer Institute (IT)
- University of Milan (IT)
- Azienda Socio Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda (IT)
- Corresponding author
- Bardelli, Alberto
- ORCID
- Sogari, Alberto
- Rovera, Emanuele
- Grasso, Gaia
- Mariella, Elisa
- Reilly, Nicole Megan
- Lamba, Simona
- Mauri, Gianluca
- Vitiello, Pietro Paolo
- Lorenzato, Annalisa
- Avolio, Marco
- Piumatti, Eleonora
- Bonoldi, Emanuela
- Aquilano, Maria Costanza
- Arena, Sabrina
- Siena, Salvatore
- Trusolino, Livio
- Russo, Mariangela
- Lembo, David
- Bardelli, Alberto
- Venue
- Cell Reports Medicine
- Publisher
- Elsevier BV
- Published
- 2024-02
- Volume
- 5
- Issue
- 2
- Pages
- 101376
- ISSN
- 2666-3791 (ISSN-L)
- PMC
- PMC10897517
- OpenAlex
- W4390877039
- Cited by
- 17
- References
- 58
- Citations by year
- 2026: 6 · 2025: 5 · 2024: 6
- FWCI
- 2.31
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports Medicine (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion, cc-by-nc-nd)
- Funders
- Cancer Research UK (A28223, A26825, 27321, 22795)
- European Commission (101058620, 754923, HORIZON2020, H2020)
- Ministero della Salute ("5 x 1000"., 21091)
- Ministero dell’Istruzione, dell’Università e della Ricerca (2022LSFKWE, H2020, 5x1000)
- Associazione Italiana per la Ricerca sul Cancro (MFAG 2021 - ID 26439, IG-2018, 20236, MFAG 2021, 5X 1000, MFAG 2017, 22802, 21091, 21923, 22795)
- Fondazione Italiana per la Ricerca sul Cancro (22795, 21923)
- Horizon 2020 Framework Programme (754923, 101058620, 101020342)
- HORIZON EUROPE Framework Programme (754923)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer therapeutics and mechanisms
- Keywords
- colibactin, colorectal cancer, homologous recombination, irinotecan, SN-38, chemoresistance, ATM, DNA double-strand break repair, bacterial genotoxins, patient-derived organoids, DNA repair
- MeSH terms
- Irinotecan, DNA, Escherichia coli, Humans, Peptides, Retrospective Studies, Colorectal Neoplasms, Polyketides
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