Genomic aberrations after short-term exposure to colibactin-producing E. coli transform primary colon epithelial cells
Genotoxic colibactin-producing pks+ Escherichia coli induce DNA double-strand breaks, mutations, and promote tumor development in mouse models of colorectal cancer (CRC). Colibactin’s distinct mutational signature is reflected in human CRC, suggesting a causal link. Here, we investigate its transfor...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
Nature Research
2021
|
| _version_ | 1797098078971363328 |
|---|---|
| author | Iftekhar, A Berger, H Bouznad, N Heuberger, J Boccellato, F Dobrindt, U Hermeking, H Sigal, M Meyer, TF |
| author_facet | Iftekhar, A Berger, H Bouznad, N Heuberger, J Boccellato, F Dobrindt, U Hermeking, H Sigal, M Meyer, TF |
| author_sort | Iftekhar, A |
| collection | OXFORD |
| description | Genotoxic colibactin-producing pks+ Escherichia coli induce DNA double-strand breaks, mutations, and promote tumor development in mouse models of colorectal cancer (CRC). Colibactin’s distinct mutational signature is reflected in human CRC, suggesting a causal link. Here, we investigate its transformation potential using organoids from primary murine colon epithelial cells. Organoids recovered from short-term infection with pks+ E. coli show characteristics of CRC cells, e.g., enhanced proliferation, Wnt-independence, and impaired differentiation. Sequence analysis of Wnt-independent organoids reveals an enhanced mutational burden, including chromosomal aberrations typical of genomic instability. Although we do not find classic Wnt-signaling mutations, we identify several mutations in genes related to p53-signaling, including miR-34a. Knockout of Trp53 or miR-34 in organoids results in Wnt-independence, corroborating a functional interplay between the p53 and Wnt pathways. We propose larger chromosomal alterations and aneuploidy as the basis of transformation in these organoids, consistent with the early appearance of chromosomal instability in CRC.
|
| first_indexed | 2024-03-07T05:04:31Z |
| format | Journal article |
| id | oxford-uuid:d974dcfc-30ab-4814-83a1-ff504181d03f |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T05:04:31Z |
| publishDate | 2021 |
| publisher | Nature Research |
| record_format | dspace |
| spelling | oxford-uuid:d974dcfc-30ab-4814-83a1-ff504181d03f2022-03-27T08:56:05ZGenomic aberrations after short-term exposure to colibactin-producing E. coli transform primary colon epithelial cellsJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:d974dcfc-30ab-4814-83a1-ff504181d03fEnglishSymplectic ElementsNature Research2021Iftekhar, ABerger, HBouznad, NHeuberger, JBoccellato, FDobrindt, UHermeking, HSigal, MMeyer, TFGenotoxic colibactin-producing pks+ Escherichia coli induce DNA double-strand breaks, mutations, and promote tumor development in mouse models of colorectal cancer (CRC). Colibactin’s distinct mutational signature is reflected in human CRC, suggesting a causal link. Here, we investigate its transformation potential using organoids from primary murine colon epithelial cells. Organoids recovered from short-term infection with pks+ E. coli show characteristics of CRC cells, e.g., enhanced proliferation, Wnt-independence, and impaired differentiation. Sequence analysis of Wnt-independent organoids reveals an enhanced mutational burden, including chromosomal aberrations typical of genomic instability. Although we do not find classic Wnt-signaling mutations, we identify several mutations in genes related to p53-signaling, including miR-34a. Knockout of Trp53 or miR-34 in organoids results in Wnt-independence, corroborating a functional interplay between the p53 and Wnt pathways. We propose larger chromosomal alterations and aneuploidy as the basis of transformation in these organoids, consistent with the early appearance of chromosomal instability in CRC. |
| spellingShingle | Iftekhar, A Berger, H Bouznad, N Heuberger, J Boccellato, F Dobrindt, U Hermeking, H Sigal, M Meyer, TF Genomic aberrations after short-term exposure to colibactin-producing E. coli transform primary colon epithelial cells |
| title | Genomic aberrations after short-term exposure to colibactin-producing E. coli transform primary colon epithelial cells |
| title_full | Genomic aberrations after short-term exposure to colibactin-producing E. coli transform primary colon epithelial cells |
| title_fullStr | Genomic aberrations after short-term exposure to colibactin-producing E. coli transform primary colon epithelial cells |
| title_full_unstemmed | Genomic aberrations after short-term exposure to colibactin-producing E. coli transform primary colon epithelial cells |
| title_short | Genomic aberrations after short-term exposure to colibactin-producing E. coli transform primary colon epithelial cells |
| title_sort | genomic aberrations after short term exposure to colibactin producing e coli transform primary colon epithelial cells |
| work_keys_str_mv | AT iftekhara genomicaberrationsaftershorttermexposuretocolibactinproducingecolitransformprimarycolonepithelialcells AT bergerh genomicaberrationsaftershorttermexposuretocolibactinproducingecolitransformprimarycolonepithelialcells AT bouznadn genomicaberrationsaftershorttermexposuretocolibactinproducingecolitransformprimarycolonepithelialcells AT heubergerj genomicaberrationsaftershorttermexposuretocolibactinproducingecolitransformprimarycolonepithelialcells AT boccellatof genomicaberrationsaftershorttermexposuretocolibactinproducingecolitransformprimarycolonepithelialcells AT dobrindtu genomicaberrationsaftershorttermexposuretocolibactinproducingecolitransformprimarycolonepithelialcells AT hermekingh genomicaberrationsaftershorttermexposuretocolibactinproducingecolitransformprimarycolonepithelialcells AT sigalm genomicaberrationsaftershorttermexposuretocolibactinproducingecolitransformprimarycolonepithelialcells AT meyertf genomicaberrationsaftershorttermexposuretocolibactinproducingecolitransformprimarycolonepithelialcells |