Improved detection of colibactin-induced mutations by genotoxic E. coli in organoids and colorectal cancer

Axel Rosendahl Huber; Cayetano Pleguezuelos-Manzano; Jens Puschhof; Joske Ubels; Charelle Boot; Aurelia Saftien; Mark Verheul; Laurianne T Trabut; Niels Groenen; Markus van Roosmalen; Kyanna S Ouyang; Henry Wood; Phil Quirke; Gerrit Meijer; Edwin Cuppen; Hans Clevers; Ruben van Boxtel

doi:10.1016/j.ccell.2024.02.009

Improved detection of colibactin-induced mutations by genotoxic E. coli in organoids and colorectal cancer

Axel Rosendahl Huber, Cayetano Pleguezuelos-Manzano, Jens Puschhof, Joske Ubels, Charelle Boot, Aurelia Saftien, Mark Verheul, Laurianne T Trabut, Niels Groenen, Markus van Roosmalen, Kyanna S Ouyang, Henry Wood, Phil Quirke, Gerrit Meijer, Edwin Cuppen, Hans Clevers, Ruben van Boxtel

Hubrecht Institute

Research output: Contribution to journal/periodical › Article › Scientific › peer-review

18 Citations (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	487-496.e6
Journal	Cancer Cell
Volume	42
Issue number	3
DOIs	https://doi.org/10.1016/j.ccell.2024.02.009
Publication status	Published - 11 Mar 2024

Keywords

Humans
Escherichia coli/genetics
Mutation
DNA Damage
Mutagens
Colorectal Neoplasms
Organoids
Peptides
Polyketides

Access to Document

10.1016/j.ccell.2024.02.009

Cite this

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. (2024). Improved detection of colibactin-induced mutations by genotoxic E. coli in organoids and colorectal cancer. Cancer Cell, 42(3), 487-496.e6. https://doi.org/10.1016/j.ccell.2024.02.009

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title = "Improved detection of colibactin-induced mutations by genotoxic E. coli in organoids and colorectal cancer",

abstract = "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.",

keywords = "Humans, Escherichia coli/genetics, Mutation, DNA Damage, Mutagens, Colorectal Neoplasms, Organoids, Peptides, Polyketides",

author = "{Rosendahl Huber}, Axel and Cayetano Pleguezuelos-Manzano and Jens Puschhof and Joske Ubels and Charelle Boot and Aurelia Saftien and Mark Verheul and Trabut, {Laurianne T} and Niels Groenen and {van Roosmalen}, Markus and Ouyang, {Kyanna S} and Henry Wood and Phil Quirke and Gerrit Meijer and Edwin Cuppen and Hans Clevers and {van Boxtel}, Ruben",

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doi = "10.1016/j.ccell.2024.02.009",

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Rosendahl Huber, A, Pleguezuelos-Manzano, C, Puschhof, J, Ubels, J, Boot, C, Saftien, A, Verheul, M, Trabut, LT, Groenen, N, van Roosmalen, M, Ouyang, KS, Wood, H, Quirke, P, Meijer, G, Cuppen, E, Clevers, H & van Boxtel, R 2024, 'Improved detection of colibactin-induced mutations by genotoxic E. coli in organoids and colorectal cancer', Cancer Cell, vol. 42, no. 3, pp. 487-496.e6. https://doi.org/10.1016/j.ccell.2024.02.009

TY - JOUR

T1 - Improved detection of colibactin-induced mutations by genotoxic E. coli in organoids and colorectal cancer

AU - Rosendahl Huber, Axel

AU - Pleguezuelos-Manzano, Cayetano

AU - Puschhof, Jens

AU - Ubels, Joske

AU - Boot, Charelle

AU - Saftien, Aurelia

AU - Verheul, Mark

AU - Trabut, Laurianne T

AU - Groenen, Niels

AU - van Roosmalen, Markus

AU - Ouyang, Kyanna S

AU - Wood, Henry

AU - Quirke, Phil

AU - Meijer, Gerrit

AU - Cuppen, Edwin

AU - Clevers, Hans

AU - van Boxtel, Ruben

PY - 2024/3/11

Y1 - 2024/3/11

N2 - 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.

AB - 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.

KW - Humans

KW - Escherichia coli/genetics

KW - Mutation

KW - DNA Damage

KW - Mutagens

KW - Colorectal Neoplasms

KW - Organoids

KW - Peptides

KW - Polyketides

U2 - 10.1016/j.ccell.2024.02.009

DO - 10.1016/j.ccell.2024.02.009

M3 - Article

C2 - 38471458

SN - 1535-6108

VL - 42

SP - 487-496.e6

JO - Cancer Cell

JF - Cancer Cell

IS - 3

ER -