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  • 1.
    Bergonzini, Anna
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Effects of bacterial genotoxins on immune modulation, chronic inflammation and cancer development2023Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    The intestinal microbiome of Inflammatory Bowel Disease and colorectal cancer patients is enriched in genotoxin-producing bacteria, which cause DNA damage in the host cells.

    Genotoxins have recently been identified as a novel family of effectors produced by pathogenic and commensal bacteria. At present, only three types of bacterial genotoxins have been identified: colibactin, produced by some Escherichia coli strains; cytolethal distending toxins, produced by several Gram-negative pathogens; and the typhoid toxin, produced by Salmonella enterica serovar Typhi.

    Exposure to high toxin doses activates the classical DNA damage response, which consequently blocks proliferation and eventually induces death in mammalian cells. However, exposure to low toxin doses has shown to promote classical signs of carcinogenesis in vitro, such as cell survival and acquisition of genomic instability. Despite an extensive characterization of their mode of action in vitro, we have a poor understanding of genotoxins´ role in chronic infection and, considering the genotoxic potential, of their carcinogenic capacity. To investigate further the role played by the genotoxins, we focused specifically on Salmonella Typhi, since it is the only genotoxin-producing bacterium that induces a chronic infection associated with increased risk of tumor development in humans. 

    The results presented in this thesis show that these unusual bacterial effectors are not classical toxins, but rather act as immunomodulators, highlighting a complex and tissue-specific crosstalk between two highly conserved stress responses: the immune response and the DNA damage response. 

    Our data indicate that the impact of genotoxin-producing bacteria on the modulation of the host mucosal response is still poorly characterized and suggest that the host-microbe interaction and the tissue microenvironment are the key players in determining the outcome of the infection and the toxin carcinogenic potential. 

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  • 2.
    Bergonzini, Anna
    et al.
    Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Avila-Cariño, Javier
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Lopez Chiloeches, Maria
    Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Frisan, Teresa
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    The challenge of establishing immunocompetent human intestinal 3D modelsManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Expression of typhoid toxin in Salmonella Typhimurium causes DNA damage, activating the DNA damage response (DDR), in absence of an inflammatory response in the colonic mucosa of infected mice. The anti-inflammatory effect is tissue specific and is not observed in the liver, suggesting that the local immune microenvironment modulates the DDR outcome.

    To assess the role of the immune cells in the DDR outcome induced by the genotoxigenic Salmonella, we have initiated the development of an immunocompetent 3D colonic mucosal model based on a collagen matrix containing colonic fibroblasts and different subtypes of immune cells, overlayed with colonic epithelial cells.

    Embedding of peripheral blood mononuclear cells in the collagen matrix did not influenced either the tissue integrity or the activation of the DDR, observed exclusively upon infection with the genotoxigenic strain. However, embedding of T cells, monocytes, or non-polarized macrophages altered the pattern of the DDR and the toxin specific effect was lost. Presence of macrophages was further associated with alteration of the epithelial layer integrity. This effect was infection-dependent, but not toxin specific.

    Our data demonstrated that addition of immune cells to a 3D mucosal model altered the DDR induced by a genotoxigenic bacterium, highlighting the need to develop and optimize immunocompetent in vitro models.

  • 3.
    Lagopati, Nefeli
    et al.
    Laboratory of Histology-Embryology, Molecular Carcinogenesis Group, Medical School, National and Kapodistrian University of Athens, Athens, Greece; Laboratory of General Chemistry, School of Chemical Engineering, National Technical University of Athens, Zografou Campus, Athens, Greece; Biomedical Research Foundation Academy of Athens, Athens, Greece.
    Kotsinas, Athanassios
    Laboratory of Histology-Embryology, Molecular Carcinogenesis Group, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
    Veroutis, Dimitris
    Laboratory of Histology-Embryology, Molecular Carcinogenesis Group, Medical School, National and Kapodistrian University of Athens, Athens, Greece; Biomedical Research Foundation Academy of Athens, Athens, Greece.
    Evangelou, Konstantinos
    Laboratory of Histology-Embryology, Molecular Carcinogenesis Group, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
    Papaspyropoulos, Angelos
    Laboratory of Histology-Embryology, Molecular Carcinogenesis Group, Medical School, National and Kapodistrian University of Athens, Athens, Greece; Biomedical Research Foundation Academy of Athens, Athens, Greece.
    Arfanis, Michalis
    Institute of Nanoscience and Nanotechnology, Laboratory of Nanotechnology Processes for Solar Energy Conversion and Environmental Protection, National Centre for Scientific Research "Demokritos", Athens, Greece.
    Falaras, Polycarpos
    Institute of Nanoscience and Nanotechnology, Laboratory of Nanotechnology Processes for Solar Energy Conversion and Environmental Protection, National Centre for Scientific Research "Demokritos", Athens, Greece.
    Kitsiou, Paraskevi V.
    Institute of Biosciences and Applications, Laboratory of Biochemistry/Cell & Matrix Pathobiology, National Centre for Scientific Research "Demokritos", Athens, Greece.
    Pateras, Ioannis
    Laboratory of Histology-Embryology, Molecular Carcinogenesis Group, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
    Bergonzini, Anna
    Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Frisan, Teresa
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Kyriazis, Spyridon
    Laboratory of Histology-Embryology, Molecular Carcinogenesis Group, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
    Tsoukleris, Dimitrios S.
    Laboratory of General Chemistry, School of Chemical Engineering, National Technical University of Athens, Zografou Campus, Athens, Greece; NanoViis Company, Athens, Greece.
    Tsilibary, Effie-Photini C
    Department of Neuroscience, University of Minnesota, MN, Minneapolis, United States.
    Gazouli, Maria
    Department of Basic Medical Sciences, Laboratory of Biology, Faculty of Medicine, School of Health Science, National and Kapodistrian University of Athens, Athens, Greece.
    Pavlatou, Evangelia A.
    Laboratory of General Chemistry, School of Chemical Engineering, National Technical University of Athens, Zografou Campus, Athens, Greece; vgorg@med.uoa.gr pavlatou@chemeng.ntua.gr.
    Gorgoulis, Vassilis G.
    Biomedical Research Foundation Academy of Athens, Athens, Greece; Laboratory of Histology-Embryology, Molecular Carcinogenesis Group, Medical School, National and Kapodistrian University of Athens, Athens, Greece; vgorg@med.uoa.gr pavlatou@chemeng.ntua.gr; Faculty of Biology, Medicine and Health Manchester Cancer Research Centre, Manchester Academic Health Sciences Centre, University of Manchester, Manchester, United Kingdom; Center for New Biotechnologies and Precision Medicine, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
    Biological Effect of Silver-modified Nanostructured Titanium Dioxide in Cancer2021Ingår i: Cancer Genomics & Proteomics, ISSN 1109-6535, E-ISSN 1790-6245, Vol. 18, nr 3, s. 425-439Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND/AIM: Nanomedicine is a promising scientific field that exploits the unique properties of innovative nanomaterials, providing alternative solutions in diagnostics, prevention and therapeutics. Titanium dioxide nanoparticles (TiO2 NPs) have a great spectrum of photocatalytic antibacterial and anticancer applications. The chemical modification of TiO2 optimizes its bioactive performance. The aim of this study was the development of silver modified NPs (Ag/TiO2 NPs) with anticancer potential.

    MATERIALS AND METHODS: Ag/TiO2 NPs were prepared through the sol-gel method, were fully characterized and were tested on cultured breast cancer epithelial cells (MCF-7 and MDA-MB-231). The MTT colorimetric assay was used to estimate cellular viability. Western blot analysis of protein expression along with a DNA-laddering assay were employed for apoptosis detection.

    RESULTS AND CONCLUSION: We show that photo-activated Ag/TiO2 NPs exhibited significant cytotoxicity on the highly malignant MDA-MB-231 cancer cells, inducing apoptosis, while MCF-7 cells that are characterized by low invasive properties were unaffected under the same conditions.

  • 4.
    Lopez Chiloeches, Maria
    et al.
    Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Bergonzini, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Frisan, Teresa
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Bacterial Toxins Are a Never-Ending Source of Surprises: From Natural Born Killers to Negotiators2021Ingår i: Toxins, E-ISSN 2072-6651, Vol. 13, nr 6, artikel-id 426Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    The idea that bacterial toxins are not only killers but also execute more sophisticated roles during bacteria-host interactions by acting as negotiators has been highlighted in the past decades. Depending on the toxin, its cellular target and mode of action, the final regulatory outcome can be different. In this review, we have focused on two families of bacterial toxins: genotoxins and pore-forming toxins, which have different modes of action but share the ability to modulate the host's immune responses, independently of their capacity to directly kill immune cells. We have addressed their immuno-suppressive effects with the perspective that these may help bacteria to avoid clearance by the host's immune response and, concomitantly, limit detrimental immunopathology. These are optimal conditions for the establishment of a persistent infection, eventually promoting asymptomatic carriers. This immunomodulatory effect can be achieved with different strategies such as suppression of pro-inflammatory cytokines, re-polarization of the immune response from a pro-inflammatory to a tolerogenic state, and bacterial fitness modulation to favour tissue colonization while preventing bacteraemia. An imbalance in each of those effects can lead to disease due to either uncontrolled bacterial proliferation/invasion, immunopathology, or both.

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  • 5.
    Lopez Chiloeches, Maria
    et al.
    Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Bergonzini, Anna
    Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Frisan, Teresa
    Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Martin, Océane C.B.
    Univ. Bordeaux, INSERM, BaRITOn, U1053, Bordeaux, France.
    Characterization of macrophage infiltration and polarization by double fluorescence immunostaining in mouse colonic mucosa2021Ingår i: STAR Protocols, E-ISSN 2666-1667, Vol. 2, nr 4, artikel-id 100833Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We recently characterized the association between DNA damage and immunoresponse in vivo in colonic mucosa of mice infected with a Salmonella Typhimurium strain expressing a genotoxin, known as typhoid toxin. In this protocol, we describe how to assess the extent and features of infiltrating macrophages by double immunofluorescence. Total macrophage population was determined using an F4/80 antibody, whereas the specific M2-like population was assessed using a CD206 antibody. For complete details on the use and execution of this protocol, please refer to Martin et al. (2021).

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  • 6.
    Lopez Chiloeches, Maria
    et al.
    Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Bergonzini, Anna
    Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet). Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Martin, Océane C. B.
    Biological and Medical Sciences Department, University Bordeaux, Centre National de la Recherche Scientifique (CNRS), Institut de Biochimie et Génétique Cellulaires (IBGC), Unité Mixte de Recherche (UMR) 5095, Bordeaux, France.
    Bergstein, Nicole
    Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Erttmann, Saskia F.
    Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet). Infection Oncology Unit, Institute of Clinical Molecular Biology, Christian-Albrechts University of Kiel, Kiel, Germany.
    Aung, Kyaw Min
    Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
    Gekara, Nelson O.
    Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden; Institute of Medical Microbiology and Hygiene, Medical Center, University of Freiburg, Faculty of Medicine, Freiburg, Germany.
    Avila Cariño, Javier
    Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Pateras, Ioannis S.
    Second Department of Pathology, “Attikon” University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
    Frisan, Teresa
    Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Genotoxin-producing Salmonella enterica induces tissue-specific types of DNA damage and DNA damage response outcomes2023Ingår i: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 14, artikel-id 1270449Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Introduction: Typhoid toxin-expressing Salmonella enterica causes DNA damage in the intestinal mucosa in vivo, activating the DNA damage response (DDR) in the absence of inflammation. To understand whether the tissue microenvironment constrains the infection outcome, we compared the immune response and DDR patterns in the colon and liver of mice infected with a genotoxigenic strain or its isogenic control strain.

    Methods: In situ spatial transcriptomic and immunofluorescence have been used to assess DNA damage makers, activation of the DDR, innate immunity markers in a multiparametric analysis.

    Result: The presence of the typhoid toxin protected from colonic bacteria-induced inflammation, despite nuclear localization of p53, enhanced co-expression of type-I interferons (IfnbI) and the inflammasome sensor Aim2, both classic features of DNA-break-induced DDR activation. These effects were not observed in the livers of either infected group. Instead, in this tissue, the inflammatory response and DDR were associated with high oxidative stress-induced DNA damage.

    Conclusions: Our work highlights the relevance of the tissue microenvironment in enabling the typhoid toxin to suppress the host inflammatory response in vivo.

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  • 7. Martin, Oceane C. B.
    et al.
    Bergonzini, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
    D'Amico, Federica
    Chen, Puran
    Shay, Jerry W.
    Dupuy, Jacques
    Svensson, Mattias
    Masucci, Maria G.
    Frisan, Teresa
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet). Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
    Infection with genotoxin-producing Salmonella enterica synergises with loss of the tumour suppressor APC in promoting genomic instability via the PI3K pathway in colonic epithelial cells2019Ingår i: Cellular Microbiology, ISSN 1462-5814, E-ISSN 1462-5822, Vol. 21, nr 12, artikel-id e13099Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Several commensal and pathogenic Gram-negative bacteria produce DNA-damaging toxins that are considered bona fide carcinogenic agents. The microbiota of colorectal cancer (CRC) patients is enriched in genotoxin-producing bacteria, but their role in the pathogenesis of CRC is poorly understood. The adenomatous polyposis coli (APC) gene is mutated in familial adenomatous polyposis and in the majority of sporadic CRCs. We investigated whether the loss of APC alters the response of colonic epithelial cells to infection by Salmonella enterica, the only genotoxin-producing bacterium associated with cancer in humans. Using 2D and organotypic 3D cultures, we found that APC deficiency was associated with sustained activation of the DNA damage response, reduced capacity to repair different types of damage, including DNA breaks and oxidative damage, and failure to induce cell cycle arrest. The reduced DNA repair capacity and inability to activate adequate checkpoint responses was associated with increased genomic instability in APC-deficient cells exposed to the genotoxic bacterium. Inhibition of the checkpoint response was dependent on activation of the phosphatidylinositol 3-kinase pathway. These findings highlight the synergistic effect of the loss of APC and infection with genotoxin-producing bacteria in promoting a microenvironment conducive to malignant transformation.

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  • 8.
    Martin, Océane C.B.
    et al.
    Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
    Bergonzini, Anna
    Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Lopez Chiloeches, Maria
    Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Paparouna, Eleni
    Department of Histology and Embryology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.
    Butter, Deborah
    Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
    Theodorou, Sofia D.P.
    Department of Histology and Embryology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.
    Haykal, Maria M.
    Université Paris-Saclay, Institut Gustave Roussy, Inserm U981, Biomarqueurs prédictifs et nouvelles stratégies thérapeutiques en oncologie, Villejuif, France.
    Boutet-Robinet, Elisa
    Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRAE, ENVT, INP-Purpan, UPS, Toulouse, France.
    Tebaldi, Toma
    Center for Biomedical Data Science, Yale School of Medicine, CT, New Haven, United States.
    Wakeham, Andrew
    The Campbell Family Institute for Breast Cancer Research, Princess Margaret Hospital, University of Toronto, ON, Toronto, Canada.
    Rhen, Mikael
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Gorgoulis, Vassilis G.
    Department of Histology and Embryology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece; Biomedical Research Foundation, Academy of Athens, Athens, Greece; Institute for Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom; Manchester Centre for Cellular Metabolism, University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom.
    Mak, Tak
    The Campbell Family Institute for Breast Cancer Research, Princess Margaret Hospital, University of Toronto, ON, Toronto, Canada.
    Pateras, Ioannis S.
    Department of Histology and Embryology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.
    Frisan, Teresa
    Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet). Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
    Influence of the microenvironment on modulation of the host response by typhoid toxin2021Ingår i: Cell Reports, E-ISSN 2211-1247, Vol. 35, nr 1, artikel-id 108931Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Bacterial genotoxins cause DNA damage in eukaryotic cells, resulting in activation of the DNA damage response (DDR) in vitro. These toxins are produced by Gram-negative bacteria, enriched in the microbiota of inflammatory bowel disease (IBD) and colorectal cancer (CRC) patients. However, their role in infection remains poorly characterized. We address the role of typhoid toxin in modulation of the host-microbial interaction in health and disease. Infection with a genotoxigenic Salmonella protects mice from intestinal inflammation. We show that the presence of an active genotoxin promotes DNA fragmentation and senescence in vivo, which is uncoupled from an inflammatory response and unexpectedly associated with induction of an anti-inflammatory environment. The anti-inflammatory response is lost when infection occurs in mice with acute colitis. These data highlight a complex context-dependent crosstalk between bacterial-genotoxin-induced DDR and the host immune response, underlining an unexpected role for bacterial genotoxins.

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  • 9. Papalampros, Alexandros
    et al.
    Vailas, Michail
    Ntostoglou, Konstantinos
    Chiloeches, maria
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Sakellariou, Stratigoula
    Chouliari, Niki, V
    Samaras, Menelaos G.
    Veltsista, Paraskevi D.
    Theodorou, Sofia D. P.
    Margetis, Aggelos T.
    Bergonzini, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Karydakis, Lysandros
    Hasemaki, Natasha
    Havaki, Sophia
    Moustakas, Ioannis I.
    Chatzigeorgiou, Antonios
    Karamitros, Timokratis
    Patsea, Eleni
    Kittas, Christos
    Lazaris, Andreas C.
    Felekouras, Evangelos
    Gorgoulis, Vassilis G.
    Frisan, Teresa
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Pateras, Ioannis S.
    Unique Spatial Immune Profiling in Pancreatic Ductal Adenocarcinoma with Enrichment of Exhausted and Senescent T Cells and Diffused CD47-SIRP proportional to Expression2020Ingår i: Cancers, ISSN 2072-6694, Vol. 12, nr 7, artikel-id 1825Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Pancreatic ductal adenocarcinoma (PDAC) is resistant to single-agent immunotherapies. To understand the mechanisms leading to the poor response to this treatment, a better understanding of the PDAC immune landscape is required. The present work aims to study the immune profile in PDAC in relationship to spatial heterogeneity of the tissue microenvironment (TME) in intact tissues. Methods: Serial section and multiplex in situ analysis were performed in 42 PDAC samples to assess gene and protein expression at single-cell resolution in the: (a) tumor center (TC), (b) invasive front (IF), (c) normal parenchyma adjacent to the tumor, and (d) tumor positive and negative draining lymph nodes (LNs). Results: We observed: (a) enrichment of T cell subpopulations with exhausted and senescent phenotype in the TC, IF and tumor positive LNs; (b) a dominant type 2 immune response in the TME, which is more pronounced in the TC; (c) an emerging role of CD47-SIRP a axis; and (d) a similar immune cell topography independently of the neoadjuvant chemotherapy. Conclusion: This study reveals the existence of dysfunctional T lymphocytes with specific spatial distribution, thus opening a new dimension both conceptually and mechanistically in tumor-stroma interaction in PDAC with potential impact on the efficacy of immune-regulatory therapeutic modalities.

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  • 10.
    Pateras, Ioannis S.
    et al.
    National and Kapodistrian University of Athens, Athens, Greece.
    Igea, Ana
    Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Santiago de Compostela, Spain; Mobile Genomes, Centre for Research in Molecular Medicine and Chronic Diseases (CiMUS), University of Santiago de Compostela (USC), Santiago de Compostela, Spain.
    Nikas, Ilias P.
    Medical School, University of Cyprus, Nicosia, Cyprus.
    Leventakou, Danai
    National and Kapodistrian University of Athens, Athens, Greece.
    Koufopoulos, Nektarios I.
    National and Kapodistrian University of Athens, Athens, Greece.
    Ieronimaki, Argyro Ioanna
    National and Kapodistrian University of Athens, Athens, Greece.
    Bergonzini, Anna
    Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Alfred Nobels Allé 8, Stockholm, Sweden.
    Ryu, Han Suk
    Department of Pathology, Seoul National University Hospital, Seoul, South Korea.
    Chatzigeorgiou, Antonios
    Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
    Frisan, Teresa
    Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Kittas, Christos
    Department of Histopathology, Biomedicine Group of Health Company, Athens, Greece.
    Panayiotides, Ioannis G.
    National and Kapodistrian University of Athens, Athens, Greece.
    Diagnostic challenges during inflammation and cancer: current biomarkers and future perspectives in navigating through the minefield of reactive versus dysplastic and cancerous lesions in the digestive system2024Ingår i: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 25, nr 2, artikel-id 1251Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    In the setting of pronounced inflammation, changes in the epithelium may overlap with neoplasia, often rendering it impossible to establish a diagnosis with certainty in daily clinical practice. Here, we discuss the underlying molecular mechanisms driving tissue response during persistent inflammatory signaling along with the potential association with cancer in the gastrointestinal tract, pancreas, extrahepatic bile ducts, and liver. We highlight the histopathological challenges encountered in the diagnosis of chronic inflammation in routine practice and pinpoint tissue-based biomarkers that could complement morphology to differentiate reactive from dysplastic or cancerous lesions. We refer to the advantages and limitations of existing biomarkers employing immunohistochemistry and point to promising new markers, including the generation of novel antibodies targeting mutant proteins, miRNAs, and array assays. Advancements in experimental models, including mouse and 3D models, have improved our understanding of tissue response. The integration of digital pathology along with artificial intelligence may also complement routine visual inspections. Navigating through tissue responses in various chronic inflammatory contexts will help us develop novel and reliable biomarkers that will improve diagnostic decisions and ultimately patient treatment.

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