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  • 1. Azevedo, M
    et al.
    Eriksson, Sara
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Mendes, N
    Serpa, J
    Figueiredo, C
    Resende, LP
    Ruvoën-Clouet, N
    Haas, R
    Borén, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Le Pendu, J
    David, L
    Infection by Helicobacter pylori expressing the BabA adhesin is influenced by the secretor phenotype2008In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 215, no 3, p. 308-316Article in journal (Refereed)
    Abstract [en]

    Helicobacter pylori (Hp) infects half the world's population and causes diverse gastric lesions, from gastritis to gastric cancer. Our aim was to evaluate the significance of secretor and Lewis status in infection and in vitro adherence by Hp expressing BabA adhesin. We enrolled 304 Hp-infected individuals from Northern Portugal. Gastric biopsies, blood and saliva were collected. Polymerase chain reaction (PCR) and immunofluorescence were used to detect BabA+ Hp in gastric biopsies. In vitro adherence by a BabA expressing Hp strain to gastric biopsies was performed. Secretor status was identified by Ulex, a lectin that recognizes secretor-dependent glycan structures in saliva and in gastric mucosa, and by Lewis(a/b) antibodies, and indirectly by identification of an inactivating mutation in the FUT2 gene (G428A). BabA status of infecting Hp was associated with CagA and VacAs1 (p < 0.05), intercellular localization of Hp (p < 0.01) and the presence of intestinal metaplasia (p < 0.05) and degenerative alterations (p < 0.005) in the biopsies. BabA was associated (p < 0.05) with Ulex staining of gastric biopsies and, although not significantly, to absence of homozygosity for FUT2 G428A inactivating polymorphism. In vitro Hp adherence was higher in cases wild-type or heterozygous for FUT2 G428A mutation (p < 0.0001), cases staining for Ulex (p < 0.0001) and a(-)b+ and a(-)b(-) secretor phenotypes (p < 0.001). In conclusion, BabA+ Hp infection/adhesion is secretor-dependent and associated with the severity of gastric lesions.

  • 2. Daskalogianni, Chrysoula
    et al.
    Pyndiah, Slovenie
    Apcher, Sebastien
    Mazars, Anne
    Manoury, Benedicte
    Ammari, Nisrine
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Voisset, Cecile
    Blondel, Marc
    Fahraeus, Robin
    Epstein-Barr virus-encoded EBNA1 and ZEBRA: targets for therapeutic strategies against EBV-carrying cancers2015In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 235, no 2, p. 334-341Article, review/survey (Refereed)
    Abstract [en]

    The EBV-encoded EBNA1 was first discovered 40 years ago, approximately 10 years after the presence of EBV had been demonstrated in Burkitt's lymphoma cells. It took another 10 years before the functions of EBNA1 in maintaining the viral genome were revealed, and it has since been shown to be an essential viral factor expressed in all EBV-carrying cells. Apart from serving to maintain the viral episome and to control viral replication and gene expression, EBNA1 also harbours a cis-acting mechanism that allows virus-carrying host cells to evade the immune system. This relates to a particular glycine-alanine repeat (GAr) within EBNA1 that has the capacity to suppress antigen presentation to the major histocompatibility complex (MHC) class I pathway. We discuss the role of the GAr sequence at the level of mRNA translation initiation, rather than at the protein level, as at least part of the mechanism to avoid MHC presentation. Interfering with this mechanism has become the focus of the development of immune-based therapies against EBV-carrying cancers, and some lead compounds that affect translation of GAr-carrying mRNAs have been identified. In addition, we describe the EBV-encoded ZEBRA factor and the switch from the latent to the lytic cycle as an alternative virus-specific target for treating EBV-carrying cancers. Understanding the molecular mechanisms of how EBNA1 and ZEBRA interfere with cellular pathways not only opens new therapeutic approaches but continues to reveal new cell-biological insights on the interplay between host and virus. This review is a tale of discoveries relating to how EBNA1 and ZEBRA have emerged as targets for specific cancer therapies against EBV-carrying diseases, and serves as an illustration of how mRNA translation can play roles in future immune-based strategies to target viral disease. 

  • 3. Fehr, André
    et al.
    Hansson, Magnus C
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Kindblom, Lars-Gunnar
    Stenman, Göran
    YWHAE-FAM22 gene fusion in clear cell sarcoma of the kidney2012In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 227, no 4, p. e5-e7Article in journal (Refereed)
  • 4.
    Franklin, Oskar
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Billing, Ola
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Öhlund, Daniel
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Berglund, Anette
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Herdenberg, Carl
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Wang, Wanzhong
    Department of Pathology/Cytology, Karolinska University Hospital, Stockholm, Sweden.
    Hellman, Urban
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Novel prognostic markers within the CD44-stromal ligand network in pancreatic cancer2019In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 5, no 2, p. 130-141Article in journal (Refereed)
    Abstract [en]

    The dense stroma in pancreatic cancer tumours is rich in secreted extracellular matrix proteins and proteoglycans. Secreted hyaluronan, osteopontin and type IV collagen sustain oncogenic signalling by interactions with CD44s and its variant isoform CD44v6 on cancer cell membranes. Although well established in animal and in vitro models, this oncogenic CD44-stromal ligand network is less explored in human cancer. Here, we use a pancreatic cancer tissue microarray from 69 primary tumours and 37 metastatic lymph nodes and demonstrate that high tumour cell expression of CD44s and, surprisingly, low stromal deposition of osteopontin correlate with poor survival independent of established prognostic factors for pancreatic cancer. High stromal expression of hyaluronan was a universal trait of both primary tumours and metastatic lymph nodes. However, hyaluronan species of different molecular mass are known to function differently in pancreatic cancer biology and immunohistochemistry cannot distinguish between them. Using gas-phase electrophoretic molecular mobility analysis, we uncover a shift towards high molecular mass hyaluronan in pancreatic cancer tissue compared to normal pancreas and at a transcriptional level, we find that hyaluronan synthesising HAS2 correlates positively with CD44. The resulting prediction that high molecular mass hyaluronan would then correlate with poor survival in pancreatic cancer was confirmed in serum samples, where we demonstrate that hyaluronan >27 kDa measured before surgery is an independent predictor of postoperative survival. Our findings confirm the prognostic value of CD44 tissue expression and highlight osteopontin tissue expression and serum high molecular mass hyaluronan as novel prognostic markers in pancreatic cancer.

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  • 5. Galon, Jerome
    et al.
    Mlecnik, Bernhard
    Bindea, Gabriela
    Angell, Helen K.
    Berger, Anne
    Lagorce, Christine
    Lugli, Alessandro
    Zlobec, Inti
    Hartmann, Arndt
    Bifulco, Carlo
    Nagtegaal, Iris D.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Masucci, Giuseppe V.
    Botti, Gerardo
    Tatangelo, Fabiana
    Delrio, Paolo
    Maio, Michele
    Laghi, Luigi
    Grizzi, Fabio
    Asslaber, Martin
    D'Arrigo, Corrado
    Vidal-Vanaclocha, Fernando
    Zavadova, Eva
    Chouchane, Lotfi
    Ohashi, Pamela S.
    Hafezi-Bakhtiari, Sara
    Wouters, Bradly G.
    Roehrl, Michael
    Nguyen, Linh
    Kawakami, Yutaka
    Hazama, Shoichi
    Okuno, Kiyotaka
    Ogino, Shuji
    Gibbs, Peter
    Waring, Paul
    Sato, Noriyuki
    Torigoe, Toshihiko
    Itoh, Kyogo
    Patel, Prabhu S.
    Shukla, Shilin N.
    Wang, Yili
    Kopetz, Scott
    Sinicrope, Frank A.
    Scripcariu, Viorel
    Ascierto, Paolo A.
    Marincola, Francesco M.
    Fox, Bernard A.
    Pages, Franck
    Towards the introduction of the 'Immunoscore' in the classification of malignant tumours2014In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 232, no 2, p. 199-209Article, review/survey (Refereed)
    Abstract [en]

    The American Joint Committee on Cancer/Union Internationale Contre le Cancer (AJCC/UICC) TNM staging system provides the most reliable guidelines for the routine prognostication and treatment of colorectal carcinoma. This traditional tumour staging summarizes data on tumour burden (T), the presence of cancer cells in draining and regional lymph nodes (N) and evidence for distant metastases (M). However, it is now recognized that the clinical outcome can vary significantly among patients within the same stage. The current classification provides limited prognostic information and does not predict response to therapy. Multiple ways to classify cancer and to distinguish different subtypes of colorectal cancer have been proposed, including morphology, cell origin, molecular pathways, mutation status and gene expression-based stratification. These parameters rely on tumour-cell characteristics. Extensive literature has investigated the host immune response against cancer and demonstrated the prognostic impact of the in situ immune cell infiltrate in tumours. A methodology named Immunoscore' has been defined to quantify the in situ immune infiltrate. In colorectal cancer, the Immunoscore may add to the significance of the current AJCC/UICC TNM classification, since it has been demonstrated to be a prognostic factor superior to the AJCC/UICC TNM classification. An international consortium has been initiated to validate and promote the Immunoscore in routine clinical settings. The results of this international consortium may result in the implementation of the Immunoscore as a new component for the classification of cancer, designated TNM-I (TNM-Immune).

  • 6.
    Gu, Xiaolian
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wang, Lixiao
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Coates, Philip J.
    Research Centre for Applied Molecular Oncology (RECAMO), Masaryk Memorial Cancer Institute, Brno, Czech Republic.
    Gnanasundram, Sivakumar Vadivel
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Sgaramella, Nicola
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Sörlin, Jonas
    Clinical Genetics, Laboratory Medicine, Norrlands Universitetssjukhus, Umeå, Sweden.
    Erdogan, Baris
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Magan, Mustafa
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Evidence for etiologic field changes in tongue distant from tumor in patients with squamous cell carcinoma of the oral tongue2023In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 259, no 1, p. 93-102Article in journal (Refereed)
    Abstract [en]

    Oral cancer is a paradigm of Slaughter's concept of field cancerization, where tumors are thought to originate within an area of cells containing genetic alterations that predispose to cancer development. The field size is unclear but may represent a large area of tissue, and the origin of mutations is also unclear. Here, we analyzed whole exome and transcriptome features in contralateral tumor-distal tongue (i.e. distant from the tumor, not tumor-adjacent) and corresponding tumor tissues of 15 patients with squamous cell carcinoma of the oral tongue. The number of point mutations ranged from 41 to 237 in tumors and from one to 78 in tumor-distal samples. Tumor-distal samples showed mainly clock-like (associated with aging) or tobacco smoking mutational signatures. Tumors additionally showed mutations that associate with cytidine deaminase AID/APOBEC enzyme activities or a UV-like signature. Importantly, no point mutations were shared between a tumor and the matched tumor-distal sample in any patient. TP53 was the most frequently mutated gene in tumors (67%), whereas a TP53 mutation was detected in only one tumor-distal sample, and this mutation was not shared with the matched tumor. Arm-level copy number variation (CNV) was found in 12 tumors, with loss of chromosome (Chr) 8p or gain of 8q being the most frequent events. Two tumor-distal samples showed a gain of Chr8, which was associated with increased expression of Chr8-located genes in these samples, although gene ontology did not show a role for these genes in oncogenic processes. In situ hybridization revealed a mixed pattern of Chr8 gain and neutral copy number in both tumor cells and adjacent nontumor epithelium in one patient. We conclude that distant field cancerization exists but does not present as tumor-related mutational events. The data are compatible with etiologic field effects, rather than classical monoclonal field cancerization theory. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

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  • 7.
    Halin Bergström, Sofia
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Rudolfsson, Stina H.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Lundholm, Marie
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Josefsson, Andreas
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Wikström, Pernilla
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    High-grade tumours promote growth of other less-malignant tumours in the same prostate2021In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 253, no 4, p. 396-403Article in journal (Refereed)
    Abstract [en]

    Prostate cancer is a multifocal disease, but if and how individual prostate tumours influence each other is largely unknown. We therefore explored signs of direct or indirect tumour–tumour interactions in experimental models and patient samples. Low‐metastatic AT1 and high‐metastatic MatLyLu (MLL) Dunning rat prostate cancer cells were injected into separate lobes of the ventral prostate of immunocompetent rats. AT1 tumours growing in the same prostate as MLL tumours had increased tumour size and proliferation compared to AT1 tumours growing alone. In addition, the vasculature and macrophage density surrounding the AT1 tumours were increased by MLL tumour closeness. In patient prostatectomy samples, selected to contain an index tumour [tumour with the highest grade, International Society of Urological Pathology (ISUP) grade 1, 2, 3 or 4] and a low‐grade satellite tumour (ISUP grade 1), cell proliferation in low‐grade satellite tumours gradually increased with increasing histological grade of the index tumour. The density of blood vessels and CD68+ macrophages also increased around the low‐grade satellite tumour if a high‐grade index tumour was present. This suggests that high‐grade tumours, by changing the prostate microenvironment, may increase the aggressiveness of low‐grade lesions in the organ. Future studies are needed to explore the mechanisms behind tumour–tumour interactions and their clinical importance.

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  • 8. Ihse, E.
    et al.
    Ybo, A.
    Suhr, Ole B.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Lindqvist, Per
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Clinical Physiology.
    Backman, Christer
    Westermark, P.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Clinical Physiology.
    Amyloid fibril composition is related to the phenotype of hereditary transthyretin V30M amyloidosis2008In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 216, no 2, p. 253-261Article in journal (Refereed)
    Abstract [en]

    Swedish familial systemic amyloidosis with polyneuropathy (FAP) depends on a mutation leading to a methionine‐for‐valine substitution in transthyretin. The disease appears with different clinical manifestations, including age of onset and involvement of the heart. Liver transplantation is currently the only curative treatment, but progressive cardiomyopathy may occur post‐transplant. Two amyloid deposition patterns have previously been described in the heart. In one, the amyloid consists partially of transthyretin fragments and is weakly stainable by Congo red, while in the other, only full‐length molecules are found and the fibrils have a strong affinity for Congo red. The present study aimed to see whether these morphological and biochemical variations have clinical implications. Subcutaneous adipose tissue biopsies were taken from 33 patients with Val30Met FAP and examined by microscopy, electrophoresis and western blot. Clinical data included age, sex, duration of disease and echocardiographic determination of the interventricular septum (IVS) thickness. It was found that fibrils composed of only full‐length transthyretin were associated with early age of onset (44.8 ± 12.9 years), no clinical cardiac involvement and a strong affinity for Congo red. In contrast, presence of transthyretin fragments in the amyloid was associated with late age of onset (67.3 ± 7.0 years), signs of cardiac involvement and weak Congo red staining. For each individual, the same molecular type of amyloid was found in different organs. This is the first report showing that variations in clinical appearance of familial ATTR amyloidosis are associated with specific structural differences in the amyloid fibrils, and therefore may have a molecular cause. The molecular type of amyloid can be determined from a subcutaneous fat tissue biopsy.

  • 9.
    Kiflemariam, Sara
    et al.
    Uppsala Univ, Dept Immunol Genet & Pathol, Sci Life Lab, Rudbeck Lab, Uppsala, Sweden.
    Mignardi, Marco
    Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Solna, Sweden.
    Ali, Muhammad Akhtar
    Uppsala Univ, Dept Immunol Genet & Pathol, Sci Life Lab, Rudbeck Lab, Uppsala, Sweden.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Nilsson, Mats
    Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Solna, Sweden.
    Sjöblom, Tobias
    Uppsala Univ, Dept Immunol Genet & Pathol, Sci Life Lab, Rudbeck Lab, Uppsala, Sweden.
    In situ sequencing identifies TMPRSS2-ERG fusion transcripts, somatic point mutations and gene expression levels in prostate cancers2014In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 234, no 2, p. 253-261Article in journal (Refereed)
    Abstract [en]

    Translocations contribute to the genesis and progression of epithelial tumours and in particular to prostate cancer development. To better understand the contribution of fusion transcripts and visualize the clonal composition of multifocal tumours, we have developed a technology for multiplex in situ detection and identification of expressed fusion transcripts. When compared to immunohistochemistry, TMPRSS2-ERG fusion-negative and fusion-positive prostate tumours were correctly classified. The most prevalent TMPRSS2-ERG fusion variants were visualized, identified, and quantitated in human prostate cancer tissues, and the ratio of the variant fusion transcripts could for the first time be directly determined by in situ sequencing. Further, we demonstrate concurrent in situ detection of gene expression, point mutations, and gene fusions of the prostate cancer relevant targets AMACR, AR, TP53, and TMPRSS2-ERG. This unified approach to in situ analyses of somatic mutations can empower studies of intra-tumoural heterogeneity and future tissue-based diagnostics of mutations and translocations. Copyright (c) 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  • 10.
    Kübler, André
    et al.
    Johns Hopkins Univ, Sch Med, Ctr TB Res, Baltimore, MD USA.
    Luna, Brian
    Johns Hopkins Univ, Sch Med, Ctr TB Res, Baltimore, MD USA.
    Larsson, Christer
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Ammerman, Nicole C
    KwaZulu Natal Res Inst TB & HIV K RITH, Durban, South Africa.
    Andrade, Bruno B
    NIAID, Immunobiol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA.
    Orandle, Marlene
    NIAID, Infect Dis Pathogenesis Sect, Comparat Med Branch, NIH, Bethesda, MD 20892 USA.
    Bock, Kevin W
    NIAID, Infect Dis Pathogenesis Sect, Comparat Med Branch, NIH, Bethesda, MD 20892 USA.
    Xu, Ziyue
    NIH, Bethesda, MD 20892 USA.
    Bagci, Ulas
    NIH, Bethesda, MD 20892 USA.
    Molura, Daniel J
    Marshall, John
    Burns, Jay
    Winglee, Kathryn
    Ahidjo, Bintou Ahmadou
    Cheung, Laurene S
    Klunk, Mariah
    Jain, Sanjay K
    Kumar, Nathella Pavan
    Babu, Subash
    Sher, Alan
    Friedland, Jon S
    Elkington, Paul T G
    Bishai, William R
    Mycobacterium tuberculosis dysregulates MMP/TIMP balance to drive rapid cavitation and unrestrained bacterial proliferation.2015In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 235, no 3, p. 431-444Article in journal (Refereed)
    Abstract [en]

    Active tuberculosis (TB) often presents with advanced pulmonary disease, including irreversible lung damage and cavities. Cavitary pathology contributes to antibiotic failure, transmission, morbidity and mortality. Matrix metalloproteinases (MMPs), in particular MMP-1 are implicated in TB pathogenesis. We explored the mechanisms relating MMP/TIMP imbalance to cavity formation in a modified rabbit model of cavitary TB. Our model results in consistent progression of consolidation to human-like cavities (100% by day 28) with resultant bacillary burdens (>10(7) CFU/g) far greater than those found in matched granulomatous tissue (10(5) CFU/g). Using a novel, breath-hold computerized tomography scanning and image analysis protocol. We show that cavities develop rapidly from areas of densely consolidated tissue. Radiological change correlated with a decrease in functional lung tissue as estimated by changes in lung density during controlled pulmonary expansion (R(2) =0.6356, p < 0.0001). We demonstrated that the expression of interstitial collagenase (MMP-1) is specifically greater in cavitary compared to granulomatous lesions (p < 0.01), and that TIMP-3 significantly decreases at the cavity surface. Our findings demonstrate that an MMP-1/TIMP imbalance, is associated with the progression of consolidated regions to cavities containing very high bacterial burdens. Our model provided mechanistic insight, correlating with human disease at the pathological, microbiological and molecular levels,. It also provides a strategy to investigate therapeutics in the context of complex TB pathology. We used these findings to predict a MMP/TIMP balance in active TB; and confirmed this in human plasma, revealing the potential of MMP/TIMP levels as key components of a diagnostic matrix aimed at distinguishing active from latent TB (PPV=92.9%; 95%CI 66.1-99.8%, NPV=85.6%; 95%CI 77.0-91.9%).

  • 11. Morin, Eric
    et al.
    Sjöberg, Elin
    Tjomsland, Vegard
    Testini, Chiara
    Lindskog, Cecilia
    Franklin, Oskar
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Öhlund, Daniel
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Umeå University, Wallenberg Centre for Molecular Medicine, Umeå, Sweden.
    Kiflemariam, Sara
    Sjöblom, Tobias
    Claesson-Welsh, Lena
    VEGF receptor-2/neuropilin 1 trans-complex formation between endothelial and tumor cells is an independent predictor of pancreatic cancer survival2018In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 246, no 3, p. 311-322Article in journal (Refereed)
    Abstract [en]

    Unstable and dysfunctional tumor vasculature promotes cancer progression and spread. Signal transduction by the pro-angiogenic vascular endothelial growth factor (VEGF) receptor-2 (VEGFR2) is modulated by VEGFA-dependent complex formation with neuropilin 1 (NRP1). NRP1 expressed on tumor cells can form VEGFR2/NRP1 trans-complexes between tumor cells and endothelial cells which arrests VEGFR2 on the endothelial surface, thus interfering with productive VEGFR2 signaling. In mouse fibrosarcoma, VEGFR2/NRP1 trans-complexes correlated with reduced tumor vessel branching and reduced tumor cell proliferation. Pancreatic ductal adenocarcinoma (PDAC) strongly expressed NRP1 on both tumor cells and endothelial cells, in contrast to other common cancer forms. Using proximity ligation assay, VEGFR2/NRP1 trans-complexes were identified in human PDAC tumor tissue, and its presence was associated with reduced tumor vessel branching, reduced tumor cell proliferation, and improved patient survival after adjusting for other known survival predictors. We conclude that VEGFR2/NRP1 trans-complex formation is an independent predictor of PDAC patient survival. 

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  • 12.
    Quilichini, Evans
    et al.
    Centre National de la Recherche Scientifique (CNRS), UMR7622, Institut de Biologie Paris-Seine (IBPS), Paris, France.
    Fabre, Mélanie
    Centre National de la Recherche Scientifique (CNRS), UMR7622, Institut de Biologie Paris-Seine (IBPS), Paris, France.
    Nord, Christoffer
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Dirami, Thassadite
    Centre National de la Recherche Scientifique (CNRS), UMR7622, Institut de Biologie Paris-Seine (IBPS), Paris, France; Sorbonne Université, UMR7622-IBPS, Paris, France.
    Le Marec, Axelle
    Centre National de la Recherche Scientifique (CNRS), UMR7622, Institut de Biologie Paris-Seine (IBPS), Paris, France; Sorbonne Université, UMR7622-IBPS, Paris, France.
    Cereghini, Silvia
    Centre National de la Recherche Scientifique (CNRS), UMR7622, Institut de Biologie Paris-Seine (IBPS), Paris, France; Sorbonne Université, UMR7622-IBPS, Paris, France.
    Pasek, Raymond C
    Department of Medicine, Vanderbilt University Medical Center, TN, Nashville, United States.
    Gannon, Maureen
    Department of Medicine, Vanderbilt University Medical Center, TN, Nashville, United States.
    Ahlgren, Ulf
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Haumaitre, Cécile
    Centre National de la Recherche Scientifique (CNRS), UMR7622, Institut de Biologie Paris-Seine (IBPS), Paris, France; Sorbonne Université, UMR7622-IBPS, Paris, France.
    Insights into the etiology and physiopathology of MODY5/HNF1B pancreatic phenotype with a mouse model of the human disease2021In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 254, no 1, p. 31-45Article in journal (Refereed)
    Abstract [en]

    Maturity‐onset diabetes of the young type 5 (MODY5) is due to heterozygous mutations or deletion of HNF1B. No mouse models are currently available to recapitulate the human MODY5 disease. Here, we investigate the pancreatic phenotype of a unique MODY5 mouse model generated by heterozygous insertion of a human HNF1B splicing mutation at the intron‐2 splice donor site in the mouse genome. This Hnf1bsp2/+ model generated with targeted mutation of Hnf1b mimicking the c.544+1G>T (<IVS2nt+1G>T) mutation identified in humans, results in alternative transcripts and a 38% decrease of native Hnf1b transcript levels. As a clinical feature of MODY5 patients, the hypomorphic mouse model Hnf1bsp2/+ displays glucose intolerance. Whereas Hnf1bsp2/+ isolated islets showed no altered insulin secretion, we found a 65% decrease in pancreatic insulin content associated with a 30% decrease in total large islet volume and a 20% decrease in total β‐cell volume. These defects were associated with a 30% decrease in expression of the pro‐endocrine gene Neurog3 that we previously identified as a direct target of Hnf1b, showing a developmental etiology. As another clinical feature of MODY5 patients, the Hnf1bsp2/+ pancreases display exocrine dysfunction with hypoplasia. We observed chronic pancreatitis with loss of acinar cells, acinar‐to‐ductal metaplasia, and lipomatosis, with upregulation of signaling pathways and impaired acinar cell regeneration. This was associated with ductal cell deficiency characterized by shortened primary cilia. Importantly, the Hnf1bsp2/+ mouse model reproduces the pancreatic features of the human MODY5/HNF1B disease, providing a unique in vivo tool for molecular studies of the endocrine and exocrine defects and to advance basic and translational research.

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  • 13.
    Salomao, Norman
    et al.
    Inserm UMRS1131, Institut de Génétique Moléculaire, Université Paris 7, Hôpital St Louis, Paris, France.
    Karakostis, Konstantinos
    Inserm UMRS1131, Institut de Génétique Moléculaire, Université Paris 7, Hôpital St Louis, Paris, France.
    Hupp, Ted
    University of Gdansk, International Centre for Cancer Vaccine Science, Gdansk, Poland; University of Edinburgh, Institute of Genetics and Molecular Medicine, Edinburgh, United Kingdom.
    Vollrath, Friz
    Department of Zoology, Zoology Research and Administration Building, University of Oxford, Oxford, United Kingdom.
    Vojtesek, Borivoj
    RECAMO, Masaryk Memorial Cancer Institute, Brno, Czech Republic.
    Fåhraeus, Robin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Inserm UMRS1131, Institut de Génétique Moléculaire, Université Paris 7, Hôpital St Louis, Paris, France; University of Gdansk, International Centre for Cancer Vaccine Science, Gdansk, Poland; RECAMO, Masaryk Memorial Cancer Institute, Brno, Czech Republic.
    What do we need to know and understand about p53 to improve its clinical value?2021In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 254, no 4, p. 443-453Article, review/survey (Refereed)
    Abstract [en]

    Few proteins are more studied than the p53 tumour suppressor, but what have we learned from these studies and what do we really know about p53 that can benefit clinical practice? The DNA sequence encoding p53 is frequently mutated in cancers but the functional outcomes of single mutations, in respect to loss or gain of different activities, especially in relation to immune evasion, are not clear. This illustrates p53's complexity which even after 40 years keeps providing surprises, but also explains why it has not yet lived up to its potential to benefit cancer treatment. We have reassessed a few key experiments that shaped the p53 field and we take a closer look at the interpretations of these experiments: what they have taught us, the resulting dogmas, and their potential clinical importance. One outcome is a more dynamic view of p53 in terms of its activity, its regulation, and downstream effectors, which will benefit the clinical application of p53 for diagnosis, prognosis, and therapy. Mutations and regulatory factors can have different effects on p53 activity depending on context, important but neglected aspects when interpreting p53 and its pathways in cancers. Even though p53 is undoubtedly unique as a multifunctional hub in different cellular pathways, the concept of a factor taking up different functions within a regulatory pathway during different conditions is not. In this sense, p53 continues to lead the way for a better understanding of the cellular and molecular mechanisms underlying cancer development in vivo.

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