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Publications (10 of 40) Show all publications
Pateras, I. S., Igea, A., Nikas, I. P., Leventakou, D., Koufopoulos, N. I., Ieronimaki, A. I., . . . Panayiotides, I. G. (2024). 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 system. International Journal of Molecular Sciences, 25(2), Article ID 1251.
Open this publication in new window or tab >>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 system
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2024 (English)In: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 25, no 2, article id 1251Article, review/survey (Refereed) Published
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.

Place, publisher, year, edition, pages
MDPI, 2024
Keywords
artificial intelligence, biomarkers, cancer, digital pathology, dysplasia, immunohistochemistry, inflammation, molecular biology, pathology, reactive atypia, tissue response
National Category
Cell and Molecular Biology Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-220457 (URN)10.3390/ijms25021251 (DOI)38279253 (PubMedID)2-s2.0-85183424720 (Scopus ID)
Funder
Swedish Cancer Society, 23 2814 PjThe Kempe Foundations, 2021 JCK-3110
Available from: 2024-02-05 Created: 2024-02-05 Last updated: 2024-02-05Bibliographically approved
Chaves-Olarte, E., Meza-Torres, J., Herrera-Rodríguez, F., Lizano-González, E., Suárez-Esquivel, M., Baker, K. S., . . . Guzmán-Verri, C. (2023). A sensor histidine kinase from a plant-endosymbiont bacterium restores the virulence of a mammalian intracellular pathogen. Microbial Pathogenesis, 185, Article ID 106442.
Open this publication in new window or tab >>A sensor histidine kinase from a plant-endosymbiont bacterium restores the virulence of a mammalian intracellular pathogen
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2023 (English)In: Microbial Pathogenesis, ISSN 0882-4010, E-ISSN 1096-1208, Vol. 185, article id 106442Article in journal (Refereed) Published
Abstract [en]

Alphaproteobacteria include organisms living in close association with plants or animals. This interaction relies partly on orthologous two-component regulatory systems (TCS), with sensor and regulator proteins modulating the expression of conserved genes related to symbiosis/virulence. We assessed the ability of the exoS+Sm gene, encoding a sensor protein from the plant endosymbiont Sinorhizobium meliloti to substitute its orthologous bvrS in the related animal/human pathogen Brucella abortus. ExoS phosphorylated the B. abortus regulator BvrR in vitro and in cultured bacteria, showing conserved biological function. Production of ExoS in a B. abortus bvrS mutant reestablished replication in host cells and the capacity to infect mice. Bacterial outer membrane properties, the production of the type IV secretion system VirB, and its transcriptional regulators VjbR and BvrR were restored as compared to parental B. abortus. These results indicate that conserved traits of orthologous TCS from bacteria living in and sensing different environments are sufficient to achieve phenotypic plasticity and support bacterial survival. The knowledge of bacterial genetic networks regulating host interactions allows for an understanding of the subtle differences between symbiosis and parasitism. Rewiring these networks could provide new alternatives to control and prevent bacterial infection.

Place, publisher, year, edition, pages
Elsevier, 2023
National Category
Cell and Molecular Biology Microbiology
Identifiers
urn:nbn:se:umu:diva-222458 (URN)10.1016/j.micpath.2023.106442 (DOI)001118487100001 ()37944675 (PubMedID)2-s2.0-85177085503 (Scopus ID)
Available from: 2024-03-18 Created: 2024-03-18 Last updated: 2024-03-19Bibliographically approved
Lopez Chiloeches, M., Bergonzini, A., Martin, O. C. B., Bergstein, N., Erttmann, S. F., Aung, K. M., . . . Frisan, T. (2023). Genotoxin-producing Salmonella enterica induces tissue-specific types of DNA damage and DNA damage response outcomes. Frontiers in Immunology, 14, Article ID 1270449.
Open this publication in new window or tab >>Genotoxin-producing Salmonella enterica induces tissue-specific types of DNA damage and DNA damage response outcomes
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2023 (English)In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 14, article id 1270449Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2023
Keywords
bacterial genotoxin, DNA damage response, inflammasome, inflammation, tissue specificity
National Category
Immunology Microbiology
Identifiers
urn:nbn:se:umu:diva-220315 (URN)10.3389/fimmu.2023.1270449 (DOI)001150445700001 ()38274797 (PubMedID)2-s2.0-85183041210 (Scopus ID)
Funder
Swedish Cancer Society, 20 0699 PjFSwedish Research Council, 2021-00960The Kempe Foundations, SMK-1962The Kempe Foundations, JCK-1826The Kempe Foundations, JCK-3110Cancerforskningsfonden i Norrland, AMP20-993Cancerforskningsfonden i Norrland, AMP 17-884
Available from: 2024-02-13 Created: 2024-02-13 Last updated: 2024-02-13Bibliographically approved
Pateras, I. S., Williams, C., Gianniou, D. D., Margetis, A. T., Avgeris, M., Rousakis, P., . . . Frisan, T. (2023). Short term starvation potentiates the efficacy of chemotherapy in triple negative breast cancer via metabolic reprogramming. Journal of Translational Medicine, 21(1), Article ID 169.
Open this publication in new window or tab >>Short term starvation potentiates the efficacy of chemotherapy in triple negative breast cancer via metabolic reprogramming
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2023 (English)In: Journal of Translational Medicine, E-ISSN 1479-5876, Vol. 21, no 1, article id 169Article in journal (Refereed) Published
Abstract [en]

Background: Chemotherapy (CT) is central to the treatment of triple negative breast cancer (TNBC), but drug toxicity and resistance place strong restrictions on treatment regimes. Fasting sensitizes cancer cells to a range of chemotherapeutic agents and also ameliorates CT-associated adverse effects. However, the molecular mechanism(s) by which fasting, or short-term starvation (STS), improves the efficacy of CT is poorly characterized.

Methods: The differential responses of breast cancer or near normal cell lines to combined STS and CT were assessed by cellular viability and integrity assays (Hoechst and PI staining, MTT or H2DCFDA staining, immunofluorescence), metabolic profiling (Seahorse analysis, metabolomics), gene expression (quantitative real-time PCR) and iRNA-mediated silencing. The clinical significance of the in vitro data was evaluated by bioinformatical integration of transcriptomic data from patient data bases: The Cancer Genome Atlas (TCGA), European Genome-phenome Archive (EGA), Gene Expression Omnibus (GEO) and a TNBC cohort. We further examined the translatability of our findings in vivo by establishing a murine syngeneic orthotopic mammary tumor-bearing model.

Results: We provide mechanistic insights into how preconditioning with STS enhances the susceptibility of breast cancer cells to CT. We showed that combined STS and CT enhanced cell death and increased reactive oxygen species (ROS) levels, in association with higher levels of DNA damage and decreased mRNA levels for the NRF2 targets genes NQO1 and TXNRD1 in TNBC cells compared to near normal cells. ROS enhancement was associated with compromised mitochondrial respiration and changes in the metabolic profile, which have a significant clinical prognostic and predictive value. Furthermore, we validate the safety and efficacy of combined periodic hypocaloric diet and CT in a TNBC mouse model.

Conclusions: Our in vitro, in vivo and clinical findings provide a robust rationale for clinical trials on the therapeutic benefit of short-term caloric restriction as an adjuvant to CT in triple breast cancer treatment.

Place, publisher, year, edition, pages
BioMed Central (BMC), 2023
Keywords
Breast cancer, Caloric restriction, Fasting, Metabolic reprogramming, Mitochondria, Oncological treatment, Oxidative stress, Reactive oxygen species, Starvation, Triple negative breast cancer
National Category
Cell and Molecular Biology Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-205797 (URN)10.1186/s12967-023-03935-9 (DOI)000943526300004 ()36869333 (PubMedID)2-s2.0-85149714467 (Scopus ID)
Funder
The Kempe Foundations, JCK-1526The Kempe Foundations, KCK-1620Swedish Research Council, 2021-00960Swedish Cancer Society, 2017/315The Kempe Foundations, JCK-1826Cancerforskningsfonden i Norrland, AMP20-993Cancerforskningsfonden i Norrland, AMP 17-884
Available from: 2023-03-28 Created: 2023-03-28 Last updated: 2024-07-04Bibliographically approved
Mathiasen, S. L., Gall-Mas, L., Pateras, I. S., Theodorou, S. D. .., Namini, M. R. .., Hansen, M. B., . . . Krejsgaard, T. (2021). Bacterial genotoxins induce T cell senescence. Cell Reports, 35(10), Article ID 109220.
Open this publication in new window or tab >>Bacterial genotoxins induce T cell senescence
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2021 (English)In: Cell Reports, E-ISSN 2211-1247, Vol. 35, no 10, article id 109220Article in journal (Refereed) Published
Abstract [en]

Several types of pathogenic bacteria produce genotoxins that induce DNA damage in host cells. Accumulating evidence suggests that a central function of these genotoxins is to dysregulate the host's immune response, but the underlying mechanisms remain unclear. To address this issue, we investigated the effects of the most widely expressed bacterial genotoxin, the cytolethal distending toxin (CDT), on T cells—the key mediators of adaptive immunity. We show that CDT induces premature senescence in activated CD4 T cells in vitro and provide evidence suggesting that infection with genotoxin-producing bacteria promotes T cell senescence in vivo. Moreover, we demonstrate that genotoxin-induced senescent CD4 T cells assume a senescence-associated secretory phenotype (SASP) which, at least partly, is orchestrated by the ATM-p38 signaling axis. These findings provide insight into the immunomodulatory properties of bacterial genotoxins and uncover a putative link between bacterial infections and T cell senescence.

Place, publisher, year, edition, pages
Elsevier, 2021
Keywords
ATM, bacteria, cytolethal distending toxin, DNA damage, genotoxins, inflammation, senescence, senescence-associated secretory phenotype, T cells, typhoid toxin
National Category
Immunology
Identifiers
urn:nbn:se:umu:diva-186361 (URN)10.1016/j.celrep.2021.109220 (DOI)000659894300012 ()34107253 (PubMedID)2-s2.0-85107392013 (Scopus ID)
Funder
Novo Nordisk, NNF14OC0012345Swedish Cancer Society, CAN 2017/315Swedish Research Council, 2018-02521Cancerforskningsfonden i Norrland, AMP 17-884The Kempe Foundations, JCK-1826
Available from: 2021-07-23 Created: 2021-07-23 Last updated: 2024-01-17Bibliographically approved
Lopez Chiloeches, M., Bergonzini, A. & Frisan, T. (2021). Bacterial Toxins Are a Never-Ending Source of Surprises: From Natural Born Killers to Negotiators. Toxins, 13(6), Article ID 426.
Open this publication in new window or tab >>Bacterial Toxins Are a Never-Ending Source of Surprises: From Natural Born Killers to Negotiators
2021 (English)In: Toxins, E-ISSN 2072-6651, Vol. 13, no 6, article id 426Article, review/survey (Refereed) Published
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.

Place, publisher, year, edition, pages
MDPI, 2021
Keywords
bacterial genotoxins, pore-forming toxins, immunoregulation, cytokines, polarization immune response, innate and adaptive immunity
National Category
Immunology in the medical area Infectious Medicine Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-187370 (URN)10.3390/toxins13060426 (DOI)000665917200001 ()34204481 (PubMedID)2-s2.0-85109964915 (Scopus ID)
Funder
Swedish Cancer Society, 2017/315, 20 0699 PjFSwedish Research Council, 2018-02521The Kempe Foundations, JCK-1826Cancerforskningsfonden i Norrland, AMP20- 993, AMP 17-884
Available from: 2021-09-09 Created: 2021-09-09 Last updated: 2024-07-04Bibliographically approved
Lagopati, N., Kotsinas, A., Veroutis, D., Evangelou, K., Papaspyropoulos, A., Arfanis, M., . . . Gorgoulis, V. G. (2021). Biological Effect of Silver-modified Nanostructured Titanium Dioxide in Cancer. Cancer Genomics & Proteomics, 18(3), 425-439
Open this publication in new window or tab >>Biological Effect of Silver-modified Nanostructured Titanium Dioxide in Cancer
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2021 (English)In: Cancer Genomics & Proteomics, ISSN 1109-6535, E-ISSN 1790-6245, Vol. 18, no 3, p. 425-439Article in journal (Refereed) Published
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.

Keywords
anticancer properties, apoptosis, cytotoxicity, Nanomedicine, nanostructured titanium dioxide, photocatalysis, silver-modified titanium dioxide
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-184127 (URN)10.21873/cgp.20269 (DOI)000667611600005 ()33994365 (PubMedID)2-s2.0-85106628567 (Scopus ID)
Available from: 2021-06-10 Created: 2021-06-10 Last updated: 2023-09-05Bibliographically approved
Saccon, E., Chen, X., Mikaeloff, F., Rodriguez, J. E., Szekely, L., Vinhas, B. S., . . . Gupta, S. (2021). Cell-type-resolved quantitative proteomics map of interferon response against SARS-CoV-2. iScience, 24(5), Article ID 102420.
Open this publication in new window or tab >>Cell-type-resolved quantitative proteomics map of interferon response against SARS-CoV-2
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2021 (English)In: iScience, E-ISSN 2589-0042 , Vol. 24, no 5, article id 102420Article in journal (Refereed) Published
Abstract [en]

The commonly used laboratory cell lines are the first line of experimental models to study the pathogenicity and performing antiviral assays for emerging viruses. Here, we assessed the tropism and cytopathogenicity of the first Swedish isolate of SARS-CoV-2 in six different human cell lines, compared their growth characteristics, and performed quantitative proteomics for the susceptible cell lines. Overall, Calu-3, Caco2, Huh7, and 293FT cell lines showed a high-to-moderate level of susceptibility to SARS-CoV-2. In Caco2 cells, the virus can achieve high titers in the absence of any prominent cytopathic effect. The protein abundance profile during SARS-CoV-2 infection revealed cell-type-specific regulation of cellular pathways. Type-I interferon signaling was identified as the common dysregulated cellular response in Caco2, Calu-3, and Huh7 cells. Together, our data show cell-type specific variability for cytopathogenicity, susceptibility, and cellular response to SARS-CoV-2 and provide important clues to guide future studies.

Place, publisher, year, edition, pages
Elsevier, 2021
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-187651 (URN)10.1016/j.isci.2021.102420 (DOI)000653990500034 ()33898942 (PubMedID)
Funder
Swedish Research Council, 2017-01330Swedish Research Council, 2018-05766Swedish Research Council, 2017-03126
Available from: 2021-09-21 Created: 2021-09-21 Last updated: 2021-09-21Bibliographically approved
Lopez Chiloeches, M., Bergonzini, A., Frisan, T. & Martin, O. C. .. (2021). Characterization of macrophage infiltration and polarization by double fluorescence immunostaining in mouse colonic mucosa. STAR Protocols, 2(4), Article ID 100833.
Open this publication in new window or tab >>Characterization of macrophage infiltration and polarization by double fluorescence immunostaining in mouse colonic mucosa
2021 (English)In: STAR Protocols, E-ISSN 2666-1667, Vol. 2, no 4, article id 100833Article in journal (Refereed) Published
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).

Place, publisher, year, edition, pages
Cell Press, 2021
Keywords
Cell-based assays, In situ hybridization, Microscopy
National Category
Immunology
Identifiers
urn:nbn:se:umu:diva-202969 (URN)10.1016/j.xpro.2021.100833 (DOI)2-s2.0-85122830767 (Scopus ID)
Funder
Swedish Cancer Society, 20 0699 PjFSwedish Cancer Society, CAN 2017/315Swedish Research Council, 2018–02521Umeå UniversityThe Kempe Foundations, JCK-1826
Available from: 2023-01-14 Created: 2023-01-14 Last updated: 2023-03-24Bibliographically approved
Frisan, T. (2021). Co- and polymicrobial infections in the gut mucosa: the host-microbiota-pathogen perspective. Cellular Microbiology, 23(2), Article ID e13279.
Open this publication in new window or tab >>Co- and polymicrobial infections in the gut mucosa: the host-microbiota-pathogen perspective
2021 (English)In: Cellular Microbiology, ISSN 1462-5814, E-ISSN 1462-5822, Vol. 23, no 2, article id e13279Article, review/survey (Refereed) Published
Abstract [en]

Infections in humans occur in the context of complex niches where the pathogen interacts with both the host microenvironment and immune response, and the symbiotic microbial community. The polymicrobial nature of many human infections adds a further layer of complexity. The effect of co- or polymicrobial infections can result in enhanced severity due to pathogens cooperative interaction or reduced morbidity because one of the pathogens affects the fitness of the other(s). In this review, the concept of co-infections and polymicrobial interactions in the context of the intestinal mucosa is discussed, focusing on the interplay between the host, the microbiota and the pathogenic organisms. Specifically, we will examine examples of pathogen-cooperative versus -antagonistic behaviour during co- and polymicrobial infections. We discuss: the infection-induced modulation of the host microenvironment and immune responses; the direct modulation of the microorganism's fitness; the potentiation of inflammatory/carcinogenic conditions by polymicrobial biofilms; and the promotion of co-infections by microbial-induced DNA damage. Open questions in this very exciting field are also highlighted.

Place, publisher, year, edition, pages
John Wiley & Sons, 2021
Keywords
bacteria, co-infections, disease progression, fungi, microbiota, mucosal microenvironment, parasites, polymicrobial infections, viruses
National Category
Microbiology
Identifiers
urn:nbn:se:umu:diva-176444 (URN)10.1111/cmi.13279 (DOI)000580988900001 ()33040471 (PubMedID)2-s2.0-85093496587 (Scopus ID)
Available from: 2020-11-20 Created: 2020-11-20 Last updated: 2023-03-24Bibliographically approved
Projects
Bacterial genotoxins: an interface between infection and cancer biology [2015-02896_VR]; Umeå UniversityPathophysiology of genotoxin producing bacteria in inflammation and cancer [2018-02521_VR]; Umeå University
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-1209-0942

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