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Contribution of pks⁺ E. coli mutations to colorectal carcinogenesis.

ABSTRACT: The dominant mutational signature in colorectal cancer genomes is C > T deamination (COSMIC Signature 1) and, in a small subgroup, mismatch repair signature (COSMIC signatures 6 and 44). Mutations in common colorectal cancer driver genes are often not consistent with those signatures. Here we perform whole-genome sequencing of normal colon crypts from cancer patients, matched to a previous multi-omic tumour dataset. We analyse normal crypts that were distant vs adjacent to the cancer. In contrast to healthy individuals, normal crypts of colon cancer patients have a high incidence of pks + (polyketide synthases) E.coli (Escherichia coli) mutational and indel signatures, and this is confirmed by metagenomics. These signatures are compatible with many clonal driver mutations detected in the corresponding cancer samples, including in chromatin modifier genes, supporting their role in early tumourigenesis. These results provide evidence that pks + E.coli is a potential driver of carcinogenesis in the human gut.

SUBMITTER: Chen B

PROVIDER: S-EPMC10687070 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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Contribution of pks<sup>+</sup> E. coli mutations to colorectal carcinogenesis.

Chen Bingjie B Ramazzotti Daniele D Heide Timon T Spiteri Inmaculada I Fernandez-Mateos Javier J James Chela C Magnani Luca L Graham Trevor A TA Sottoriva Andrea A

Nature communications 20231129 1

The dominant mutational signature in colorectal cancer genomes is C > T deamination (COSMIC Signature 1) and, in a small subgroup, mismatch repair signature (COSMIC signatures 6 and 44). Mutations in common colorectal cancer driver genes are often not consistent with those signatures. Here we perform whole-genome sequencing of normal colon crypts from cancer patients, matched to a previous multi-omic tumour dataset. We analyse normal crypts that were distant vs adjacent to the cancer. In contras ...[more]

PMID: 38030613

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Project description:Background & aimsCancer-associated fibroblasts (CAFs) play an important role in colorectal cancer (CRC) progression and predict poor prognosis in CRC patients. However, the cellular origins of CAFs remain unknown, making it challenging to therapeutically target these cells. Here, we aimed to identify the origins and contribution of colorectal CAFs associated with poor prognosis.MethodsTo elucidate CAF origins, we used a colitis-associated CRC mouse model in 5 different fate-mapping mouse lines with 5-bromodeoxyuridine dosing. RNA sequencing of fluorescence-activated cell sorting-purified CRC CAFs was performed to identify a potential therapeutic target in CAFs. To examine the prognostic significance of the stromal target, CRC patient RNA sequencing data and tissue microarray were used. CRC organoids were injected into the colons of knockout mice to assess the mechanism by which the stromal gene contributes to colorectal tumorigenesis.ResultsOur lineage-tracing studies revealed that in CRC, many ACTA2+ CAFs emerge through proliferation from intestinal pericryptal leptin receptor (Lepr)+ cells. These Lepr-lineage CAFs, in turn, express melanoma cell adhesion molecule (MCAM), a CRC stroma-specific marker that we identified with the use of RNA sequencing. High MCAM expression induced by transforming growth factor β was inversely associated with patient survival in human CRC. In mice, stromal Mcam knockout attenuated orthotopically injected colorectal tumoroid growth and improved survival through decreased tumor-associated macrophage recruitment. Mechanistically, fibroblast MCAM interacted with interleukin-1 receptor 1 to augment nuclear factor κB-IL34/CCL8 signaling that promotes macrophage chemotaxis.ConclusionsIn colorectal carcinogenesis, pericryptal Lepr-lineage cells proliferate to generate MCAM+ CAFs that shape the tumor-promoting immune microenvironment. Preventing the expansion/differentiation of Lepr-lineage CAFs or inhibiting MCAM activity could be effective therapeutic approaches for CRC.

Dataset Information

Contribution of pks⁺ E. coli mutations to colorectal carcinogenesis.

Publications

Contribution of pks<sup>+</sup> E. coli mutations to colorectal carcinogenesis.

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Dataset Information

Contribution of pks+ E. coli mutations to colorectal carcinogenesis.

Publications

Contribution of pks&lt;sup&gt;+&lt;/sup&gt; E. coli mutations to colorectal carcinogenesis.

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OmicsDI is part of the ELIXIR infrastructure

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Contribution of pks⁺ E. coli mutations to colorectal carcinogenesis.

Contribution of pks<sup>+</sup> E. coli mutations to colorectal carcinogenesis.