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Publications (10 of 11) Show all publications
Lidström, T., Cumming, J., Gaur, R., Frängsmyr, L., Pateras, I., Mickert, M. J., . . . Öhlund, D. (2023). Extracellular galectin 4 drives immune evasion and promotes T-cell apoptosis in pancreatic cancer. Cancer immunology research, 11(1), 72-92
Open this publication in new window or tab >>Extracellular galectin 4 drives immune evasion and promotes T-cell apoptosis in pancreatic cancer
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2023 (English)In: Cancer immunology research, ISSN 2326-6066, Vol. 11, no 1, p. 72-92Article in journal (Refereed) Published
Abstract [en]

Pancreatic ductal adenocarcinoma (PDAC) is characterized by rich deposits of extracellular matrix (ECM), affecting the pathophysiology of the disease. Here, we identified galectin 4 (gal 4) as a cancer cell produced protein deposited into the ECM of PDAC tumors and detected high circulating levels of gal 4 in PDAC patients. In orthotopic transplantation experiments we observed increased infiltration of T-cells and prolonged survival in immunocompetent mice transplanted with cancer cells with reduced expression of gal 4. Increased survival was not observed in immunodeficient RAG1-/- mice, demonstrating that the effect was mediated by the adaptive immune system. Furthermore, by performing single-cell RNA-sequencing we found that the myeloid compartment and cancer-associated fibroblast (CAF) subtypes were altered in the transplanted tumors. Reduced gal 4 expression was associated with higher proportion of myofibroblastic CAFs and reduced numbers of inflammatory CAFs. We also found higher proportions of M1 macrophages, T-cells and antigen presenting dendritic cells in tumors with reduced gal 4 expression. Using a co-culture system, we observed that extracellular gal 4 induced apoptosis in T-cells by binding N-glycosylation residues on CD3 epsilon/delta. Hence, we show that gal 4 is involved in immune evasion and identify gal 4 as a promising drug target for overcoming immunosuppression in PDAC. 

Place, publisher, year, edition, pages
American Association for Cancer Research, 2023
Keywords
Galectin 4, pancreatic cancer, immunosuppression, extracellular matrix, drug target
National Category
Cancer and Oncology
Research subject
Immunology; Medicine; Oncology
Identifiers
urn:nbn:se:umu:diva-201042 (URN)10.1158/2326-6066.CIR-21-1088 (DOI)36478037 (PubMedID)2-s2.0-85145492684 (Scopus ID)
Funder
The Swedish Foundation for International Cooperation in Research and Higher Education (STINT), PT2015-6432Swedish Cancer Society, AMP17-877, LP18-2202, LP20-2257, LP 21-2298Swedish Research Council, 2017-01531The Kempe Foundations, JCK-1301, SMK-1765Swedish Society of Medicine, SLS-890521, SLS-786661, SLS-691681, SLS-591551Västerbotten County Council, RV-930167, VLL-643451, VLL-832001Sjöberg FoundationKnut and Alice Wallenberg FoundationMarianne and Marcus Wallenberg Foundation, MMW 2020.0189Swedish Cancer Society, CAN 2017/332, CAN 2017/827, 20 1339 PjFSwedish Cancer Society, AMP-18-919Knut and Alice Wallenberg Foundation
Note

Originally included in thesis in manuscript form. 

Available from: 2022-11-16 Created: 2022-11-16 Last updated: 2023-10-18Bibliographically approved
Nadeem, A., Nagampalli, R., Toh, E., Alam, A., Myint, S. L., Heidler, T., . . . Persson, K. (2021). A tripartite cytolytic toxin formed by Vibrio cholerae proteins with flagellum-facilitated secretion. Proceedings of the National Academy of Sciences of the United States of America, 118(47), Article ID e2111418118.
Open this publication in new window or tab >>A tripartite cytolytic toxin formed by Vibrio cholerae proteins with flagellum-facilitated secretion
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2021 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 118, no 47, article id e2111418118Article in journal (Refereed) Published
Abstract [en]

Vibrio cholerae, responsible for outbreaks of cholera disease, is a highly motile organism by virtue of a single flagellum. We describe how the flagellum facilitates the secretion of three V. cholerae proteins encoded by a hitherto-unrecognized genomic island. The proteins MakA/B/E can form a tripartite toxin that lyses erythrocytes and is cytotoxic to cultured human cells. A structural basis for the cytolytic activity of the Mak proteins was obtained by X-ray crystallography. Flagellum-facilitated secretion ensuring spatially coordinated delivery of Mak proteins revealed a role for the V. cholerae flagellum considered of particular significance for the bacterial environmental persistence. Our findings will pave the way for the development of diagnostics and therapeutic strategies against pathogenic Vibrionaceae.

National Category
Biochemistry and Molecular Biology
Research subject
Biochemistry
Identifiers
urn:nbn:se:umu:diva-191257 (URN)10.1073/pnas.2111418118 (DOI)000727697700014 ()34799450 (PubMedID)2-s2.0-85121209218 (Scopus ID)
Funder
Swedish Research Council, 2016-05009Swedish Research Council, 2018-02914Swedish Research Council, 2019-01720Swedish Research Council, 2007-08673The Kempe Foundations, SMK-1756.2The Kempe Foundations, SMK-1553The Kempe Foundations, JCK-1728Swedish Cancer Society, 2017-419The Kempe Foundations, SMK-1961Swedish Research Council
Available from: 2022-01-12 Created: 2022-01-12 Last updated: 2023-05-11Bibliographically approved
Maneshi, P., Mason, J., Dongre, M. & Öhlund, D. (2021). Targeting Tumor-Stromal Interactions in Pancreatic Cancer: Impact of Collagens and Mechanical Traits. Frontiers in Cell and Developmental Biology, 9, Article ID 787485.
Open this publication in new window or tab >>Targeting Tumor-Stromal Interactions in Pancreatic Cancer: Impact of Collagens and Mechanical Traits
2021 (English)In: Frontiers in Cell and Developmental Biology, E-ISSN 2296-634X, Vol. 9, article id 787485Article, review/survey (Refereed) Published
Abstract [en]

Pancreatic ductal adenocarcinoma (PDAC) has one of the worst outcomes among cancers with a 5-years survival rate of below 10%. This is a result of late diagnosis and the lack of effective treatments. The tumor is characterized by a highly fibrotic stroma containing distinct cellular components, embedded within an extracellular matrix (ECM). This ECM-abundant tumor microenvironment (TME) in PDAC plays a pivotal role in tumor progression and resistance to treatment. Cancer-associated fibroblasts (CAFs), being a dominant cell type of the stroma, are in fact functionally heterogeneous populations of cells within the TME. Certain subtypes of CAFs are the main producer of the ECM components of the stroma, with the most abundant one being the collagen family of proteins. Collagens are large macromolecules that upon deposition into the ECM form supramolecular fibrillar structures which provide a mechanical framework to the TME. They not only bring structure to the tissue by being the main structural proteins but also contain binding domains that interact with surface receptors on the cancer cells. These interactions can induce various responses in the cancer cells and activate signaling pathways leading to epithelial-to-mesenchymal transition (EMT) and ultimately metastasis. In addition, collagens are one of the main contributors to building up mechanical forces in the tumor. These forces influence the signaling pathways that are involved in cell motility and tumor progression and affect tumor microstructure and tissue stiffness by exerting solid stress and interstitial fluid pressure on the cells. Taken together, the TME is subjected to various types of mechanical forces and interactions that affect tumor progression, metastasis, and drug response. In this review article, we aim to summarize and contextualize the recent knowledge of components of the PDAC stroma, especially the role of different collagens and mechanical traits on tumor progression. We furthermore discuss different experimental models available for studying tumor-stromal interactions and finally discuss potential therapeutic targets within the stroma.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2021
Keywords
collagen, extracellular matrix, mechanical traits, pancreatic cancer, PDAC—pancreatic ductal adenocarcinoma, stroma
National Category
Cell and Molecular Biology Cancer and Oncology
Research subject
Oncology
Identifiers
urn:nbn:se:umu:diva-190614 (URN)10.3389/fcell.2021.787485 (DOI)34901028 (PubMedID)2-s2.0-85120962866 (Scopus ID)
Funder
EU, Horizon 2020, 861196Swedish Research Council, 2017-01531Region Västerbotten, RV-930167Region Västerbotten, VLL-832001Cancerforskningsfonden i Norrland, LP 21-2298Marianne and Marcus Wallenberg Foundation, MMW 2020.0189Swedish Cancer Society, CAN 2017/332Swedish Cancer Society, CAN 2017/827Swedish Cancer Society, 20 1339 PjF
Available from: 2021-12-20 Created: 2021-12-20 Last updated: 2022-05-13Bibliographically approved
Dongre, M., Singh, B., Aung, K. M., Larsson, P., Miftakhova, R. R., Persson, K., . . . Wai, S. N. (2018). Flagella-mediated secretion of a novel Vibrio cholerae cytotoxin affecting both vertebrate and invertebrate hosts. Communications Biology, 1, Article ID 59.
Open this publication in new window or tab >>Flagella-mediated secretion of a novel Vibrio cholerae cytotoxin affecting both vertebrate and invertebrate hosts
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2018 (English)In: Communications Biology, E-ISSN 2399-3642, Vol. 1, article id 59Article in journal (Refereed) Published
Abstract [en]

Using Caenorhabditis elegans as an infection host model for Vibrio cholerae predator interactions, we discovered a bacterial cytotoxin, MakA, whose function as a virulence factor relies on secretion via the flagellum channel in a proton motive force-dependent manner. The MakA protein is expressed from the polycistronic makDCBA (motility-associated killing factor) operon. Bacteria expressing makDCBA induced dramatic changes in intestinal morphology leading to a defecation defect, starvation and death in C. elegans. The Mak proteins also promoted V. cholerae colonization of the zebrafish gut causing lethal infection. A structural model of purified MakA at 1.9 Å resolution indicated similarities to members of a superfamily of bacterial toxins with unknown biological roles. Our findings reveal an unrecognized role for V. cholerae flagella in cytotoxin export that may contribute both to environmental spread of the bacteria by promoting survival and proliferation in encounters with predators, and to pathophysiological effects during infections.

Place, publisher, year, edition, pages
Springer Nature Publishing AG, 2018
National Category
Microbiology in the medical area
Research subject
Infectious Diseases; Molecular Biology
Identifiers
urn:nbn:se:umu:diva-155563 (URN)10.1038/s42003-018-0065-z (DOI)000461126500059 ()30271941 (PubMedID)2-s2.0-85068116757 (Scopus ID)
Available from: 2019-01-22 Created: 2019-01-22 Last updated: 2023-03-23Bibliographically approved
Vdovikova, S., Gilfillan, S., Wang, S., Dongre, M., Wai, S. N. & Hurtado, A. (2018). Modulation of gene transcription and epigenetics of colon carcinoma cells by bacterial membrane vesicles. Scientific Reports, 8, Article ID 7434.
Open this publication in new window or tab >>Modulation of gene transcription and epigenetics of colon carcinoma cells by bacterial membrane vesicles
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2018 (English)In: Scientific Reports, E-ISSN 2045-2322, Vol. 8, article id 7434Article in journal (Refereed) Published
Abstract [en]

Interactions between bacteria and colon cancer cells infuence the transcription of the host cell. Yet is it undetermined whether the bacteria itself or the communication between the host and bacteria is responsible for the genomic changes in the eukaryotic cell. Now, we have investigated the genomic and epigenetic consequences of co-culturing colorectal carcinoma cells with membrane vesicles from pathogenic bacteria Vibrio cholerae and non-pathogenic commensal bacteria Escherichia coli. Our study reveals that membrane vesicles from pathogenic and commensal bacteria have a global impact on the gene expression of colon-carcinoma cells. The changes in gene expression correlate positively with both epigenetic changes and chromatin accessibility of promoters at transcription start sites of genes induced by both types of membrane vesicles. Moreover, we have demonstrated that membrane vesicles obtained only from V. cholerae induced the expression of genes associated with epithelial cell diferentiation. Altogether, our study suggests that the observed genomic changes in host cells might be due to specifc components of membrane vesicles and do not require communication by direct contact with the bacteria.

Place, publisher, year, edition, pages
Nature Publishing Group, 2018
National Category
Cell Biology Microbiology
Research subject
Biochemistry
Identifiers
urn:nbn:se:umu:diva-148768 (URN)10.1038/s41598-018-25308-9 (DOI)000431737300120 ()2-s2.0-85046858645 (Scopus ID)
Available from: 2018-06-15 Created: 2018-06-15 Last updated: 2023-03-23Bibliographically approved
Askarian, F., Lapek, J. D. ., Dongre, M., Tsai, C.-M., Kumaraswamy, M., Kousha, A., . . . Johannessen, M. (2018). Staphylococcus aureus Membrane-Derived Vesicles Promote Bacterial Virulence and Confer Protective Immunity in Murine Infection Models. Frontiers in Microbiology, 9, Article ID 262.
Open this publication in new window or tab >>Staphylococcus aureus Membrane-Derived Vesicles Promote Bacterial Virulence and Confer Protective Immunity in Murine Infection Models
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2018 (English)In: Frontiers in Microbiology, E-ISSN 1664-302X, Vol. 9, article id 262Article in journal (Refereed) Published
Abstract [en]

Staphylococcus aureus produces membrane-derived vesicles (MVs), which share functional properties to outer membrane vesicles. Atomic force microscopy revealed that S. aureus-derived MVs are associated with the bacterial surface or released into the surrounding environment depending on bacterial growth conditions. By using a comparative proteomic approach, a total of 131 and 617 proteins were identified in MVs isolated from S. aureus grown in Luria-Bertani and brain-heart infusion broth, respectively. Purified S. aureus MVs derived from the bacteria grown in either media induced comparable levels of cytotoxicity and neutrophil-activation. Administration of exogenous MVs increased the resistance of S. aureus to killing by whole blood or purified human neutrophils ex vivo and increased S. aureus survival in vivo. Finally, immunization of mice with S. aureus-derived MVs induced production of IgM, total IgG, IgG1, IgG2a, and IgG2b resulting in protection against subcutaneous and systemic S. aureus infection. Collectively, our results suggest S. aureus MVs can influence bacterial-host interactions during systemic infections and provide protective immunity in murine models of infection.

Keywords
Staphylococcus aureus, membrane-derived vesicles, proteomics, systemic infection, protective munity
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-145584 (URN)10.3389/fmicb.2018.00262 (DOI)000425512900001 ()2-s2.0-85042235156 (Scopus ID)
Funder
Swedish Research Council, 2013-2392Swedish Research Council, 2014-4401
Available from: 2018-03-26 Created: 2018-03-26 Last updated: 2024-01-17Bibliographically approved
Elluri, S., Enow Oben Ayuk, C., Vdovikova, S., Rompikuntal, P. K., Dongre, M., Carlsson, S., . . . Wai, S. N. (2014). Outer membrane vesicles mediate transport of biologically active Vibrio cholerae cytolysin (VCC) from V. cholerae strains. PLOS ONE, 9(9), Article ID e106731.
Open this publication in new window or tab >>Outer membrane vesicles mediate transport of biologically active Vibrio cholerae cytolysin (VCC) from V. cholerae strains
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2014 (English)In: PLOS ONE, E-ISSN 1932-6203, Vol. 9, no 9, article id e106731Article in journal (Refereed) Published
Abstract [en]

Background Outer membrane vesicles (OMVs) released from Gram-negative bacteria can serve as vehicles for the translocation of virulence factors. Vibrio cholerae produce OMVs but their putative role in translocation of effectors involved in pathogenesis has not been well elucidated. The V. cholerae cytolysin (VCC), is a pore-forming toxin that lyses target eukaryotic cells by forming transmembrane oligomeric β-barrel channels. It is considered a potent toxin that contributes to V. cholerae pathogenesis. The mechanisms involved in the secretion and delivery of the VCC have not been extensively studied.

Methodology/Principal Findings OMVs from V. cholerae strains were isolated and purified using a differential centrifugation procedure and Optiprep centrifugation. The ultrastructure and the contents of OMVs were examined under the electron microscope and by immunoblot analyses respectively. We demonstrated that VCC from V. cholerae strain V:5/04 was secreted in association with OMVs and the release of VCC via OMVs is a common feature among V. cholerae strains. The biological activity of OMV-associated VCC was investigated using contact hemolytic assay and epithelial cell cytotoxicity test. It showed toxic activity on both red blood cells and epithelial cells. Our results indicate that the OMVs architecture might play a role in stability of VCC and thereby can enhance its biological activities in comparison with the free secreted VCC. Furthermore, we tested the role of OMV-associated VCC in host cell autophagy signalling using confocal microscopy and immunoblot analysis. We observed that OMV-associated VCC triggered an autophagy response in the target cell and our findings demonstrated for the first time that autophagy may operate as a cellular defence mechanism against an OMV-associated bacterial virulence factor.

Conclusion/Significance Biological assays of OMVs from the V. cholerae strain V:5/04 demonstrated that OMV-associated VCC is indeed biologically active and induces toxicity on mammalian cells and furthermore can induce autophagy.

Place, publisher, year, edition, pages
Public library of science, 2014
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-93659 (URN)10.1371/journal.pone.0106731 (DOI)000341271500078 ()25187967 (PubMedID)2-s2.0-84907099587 (Scopus ID)
Funder
Swedish Research Council, 2006-4702Swedish Research Council, 2013-2392Swedish Research Council, 353-2010-7074Swedish Research Council, 2010-3031Swedish Research Council, 2012-4638Swedish Research Council, 349-2007-8673The Swedish Foundation for International Cooperation in Research and Higher Education (STINT), IG2008-2049
Available from: 2014-09-29 Created: 2014-09-29 Last updated: 2023-03-24Bibliographically approved
Dongre, M. & Wai, S. N. (2013). The Protease of Vibrio cholerae (PrtV) (3ed.). In: Neil D. Rawlings, Guy Salvesen (Ed.), Handbook of proteolytic enzymes: volume 1 (pp. 1219-1225). Elsevier, 1
Open this publication in new window or tab >>The Protease of Vibrio cholerae (PrtV)
2013 (English)In: Handbook of proteolytic enzymes: volume 1 / [ed] Neil D. Rawlings, Guy Salvesen, Elsevier, 2013, 3, Vol. 1, p. 1219-1225Chapter in book (Refereed)
Abstract [en]

The third edition of the Handbook of Proteolytic Enzymes aims to be a comprehensive reference work for the enzymes that cleave proteins and peptides, and contains over 850 chapters. Each chapter is organized into sections describing the name and history, activity and specificity, structural chemistry, preparation, biological aspects, and distinguishing features for a specific peptidase. The subject of Chapter 273 is The Protease of Vibrio cholerae (PrtV). Keywords Auto-proteolysis, Caenorhabditis elegans, cytokine induction, fibrinogen, fibronectin, HapR. Vibrio cholerae cytolysin (VCC), M6-peptidase family, plasminogen, polycystic kidney disease (PKD) domains, Quorum Sensing (QS), zinc-dependent metalloproteases.

Place, publisher, year, edition, pages
Elsevier, 2013 Edition: 3
National Category
Biochemistry and Molecular Biology Microbiology
Identifiers
urn:nbn:se:umu:diva-148695 (URN)9780124077447 (ISBN)
Available from: 2018-06-11 Created: 2018-06-11 Last updated: 2019-10-07Bibliographically approved
Bielig, H., Dongre, M., Zurek, B., Wai, S. N. & Kufer, T. A. (2011). A role for quorum sensing in regulating innate immune responses mediated by Vibrio cholerae outer membrane vesicles (OMVs). Gut microbes, 2(5), 274-279
Open this publication in new window or tab >>A role for quorum sensing in regulating innate immune responses mediated by Vibrio cholerae outer membrane vesicles (OMVs)
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2011 (English)In: Gut microbes, ISSN 1949-0976, E-ISSN 1949-0984, Vol. 2, no 5, p. 274-279Article in journal (Refereed) Published
Abstract [en]

Outer membrane vesicles (OMVs) are released from many Gram-negative bacteria. OMVs interact with and are taken up by human cells. We and others have now showed that OMVs contain peptidoglycan, which is sensed mainly by the pattern-recognition receptor NOD1 in the cytoplasm of host cells. Vibrio cholerae is clinically important as one of the causative agents of severe dehydrating diarrhea in humans. We showed that non-O1 non-O139 V. cholerae (NOVC) strains of V. cholera produce OMVs. Of note, we revealed that NOVC can evade NOD1-mediated immune surveillance by the quorum sensing machinery. Here we review these recent findings and discuss the relevance for our understanding of bacterial infections and innate immune responses.

Place, publisher, year, edition, pages
Taylor & Francis, 2011
Keywords
OMVs, innate immunity, peptidoglycan, NLR, Vibrio cholerae
National Category
Immunology
Identifiers
urn:nbn:se:umu:diva-146691 (URN)10.4161/gmic.2.5.18091 (DOI)000525657300002 ()22067940 (PubMedID)2-s2.0-83255175055 (Scopus ID)
Available from: 2018-04-17 Created: 2018-04-17 Last updated: 2023-10-26Bibliographically approved
Dongre, M., Uhlin, B. E. & Wai, S. N. (2011). Bacterial nanotubes for intimate sharing. Frontiers in microbiology, 2, 108
Open this publication in new window or tab >>Bacterial nanotubes for intimate sharing
2011 (English)In: Frontiers in microbiology, ISSN 1664-302X, Vol. 2, p. 108-Article in journal (Refereed) Published
Place, publisher, year, edition, pages
Frontiers Media, 2011
Keywords
filament formation, budding yeast, saccharomyces-cerevisiae, organization, tubulin, actin, localization, cytoskeleton, interphase, dynamics
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-56528 (URN)10.3389/fmicb.2011.00108 (DOI)21747808 (PubMedID)2-s2.0-84875289296 (Scopus ID)
Note

A commentary on Intercellular nanotubes mediate bacterial communication by Dubey, G. P., and Ben-Yehuda, S. (2011). Cell 144, 590–600.

Available from: 2012-06-20 Created: 2012-06-20 Last updated: 2023-03-23Bibliographically approved
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