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Rôle de l’autophagie dans la susceptibilité de l’hôte à l’infection par des Escherichia coli producteurs de colibactine associés au cancer colorectal

Abstract : Colibactin-producing strains of Escherichia coli, called CoPEC for Colibactin-producing E.coli, have emerged as major players involved in the pathogenicity of colorectal cancer (CRC). CoPEC induce DNA damage and chromosomal instability in eukaryotic cells that promote colorectal carcinogenesis in mouse models of CRC development. We have shown in a previous study that autophagy in intestinal epithelial cells (IEC) limits the pro-carcinogenic effects of CoPEC in a genetically susceptible mouse model, ApcMin/+. The first objective of the thesis was to investigate whether CoPECs are able to induce tumor development in a mouse model of CRC associated with chronic inflammation that does not exhibit genetic susceptibility or use of carcinogens. We showed that infection with CoPEC strain 11G5 or the colibactin-deficient strain, clinical and inflammatory scores are increased in wild-type mice and accentuated upon autophagy deficiency in ILCs. Infection with the 11G5 strain but not with the mutant promotes the development of invasive carcinomas, which is increased upon autophagy deficiency. The formation of invasive carcinoma is associated with the accumulation of DNA damage, independently of inflammation. In conclusion, CoPEC induce colorectal carcinogenesis in a mouse model of CRC associated with chronic inflammation without genetic susceptibility or the use of carcinogenic agents. As myeloid cells (MCs) are an important component of the tumor microenvironment, our second objective was to examine the role of autophagy within these cells in colorectal tumorigenesis in ApcMin/+ mice to CoPEC infection. We show that autophagy deficiency in MCs increases the volume but not the number of colorectal tumors in ApcMin/+ mice following infection with the 11G5 strain but not the 11G5ΔclbQ mutant strain. This is accompanied by increased cytokine production, deregulation of gene expression related to the infiltrating T-cell response, and accelerated colonic cell proliferation. In BMDM (Bone Marrow-Derived Macrophages), autophagy impairment leads to an increase in intracellular 11G5 numbers and promotes 11G5-induced proinflammatory cytokine production, but this effect is also observed following infection with 11G5ΔclbQ. Compared with the uninfected or 11G5ΔclbQ-infected condition, 11G5 infection results in increased ROS production and IL-1β secretion by BMDMs that is promoted by the impairment of autophagy. In conclusion, autophagy in MCs is required to inhibit tumor growth in the ApcMin/+ mouse model infected with CoPECs. Preliminary data suggest that this may be mediated by inhibition of CoPEC-induced ROS production, which are important regulators of IL-1β secretion and T cell response in the tumor microenvironment.
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Submitted on : Monday, May 2, 2022 - 2:54:16 PM
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2021UCFAC077_SALESSE.pdf
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  • HAL Id : tel-03656917, version 1

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Laurène Salesse. Rôle de l’autophagie dans la susceptibilité de l’hôte à l’infection par des Escherichia coli producteurs de colibactine associés au cancer colorectal. Biologie cellulaire. Université Clermont Auvergne, 2021. Français. ⟨NNT : 2021UCFAC077⟩. ⟨tel-03656917⟩

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