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  • 1. Benedito, Rui
    et al.
    Hellström, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Notch as a hub for signaling in angiogenesis2013In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 319, no 9, p. 1281-1288Article, review/survey (Refereed)
  • 2.
    Egaña, Isabel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Kaito, Hiroshi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Nitzsche, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Becker, Lore
    German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany.; Department of Neurology, Friedrich-Baur-Institut, Ludwig-Maximilians-Universität München, Munich, Germany.
    Ballester-Lopez, Carolina
    German Res Ctr Environm Hlth GmbH, Helmholtz Zentrum Munchen, Inst Expt Genet, German Mouse Clin, Neuherberg, Germany.; German Ctr Lung Res DZL, Comprehens Pneumol Ctr, Helmholtz Zentrum Munchen, Inst Lung Biol & Dis,German Res Ctr Environm Hlth, Munich, Germany.
    Niaudet, Colin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Petkova, Milena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Liu, Wei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Vanlandewijck, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Vernaleken, Alexandra
    German Res Ctr Environm Hlth GmbH, Helmholtz Zentrum Munchen, Inst Expt Genet, German Mouse Clin, Neuherberg, Germany.; Ludwig Maximilians Univ Munchen, Friedrich Baur Inst, Dept Neurol, Munich, Germany.
    Klopstock, Thomas
    Department of Neurology, Friedrich-Baur-Institut, Ludwig-Maximilians-Universität München, Munich, Germany.; German Center for Vertigo and Balance Disorders, Munich, Germany.; Deutsches Zentrum für Neurodegenerative Erkrankungen e. V. (DZNE), Munich, Germany.; German Network for Mitochondrial Disorders (mitoNET), Munich, Germany.
    Fuchs, Helmut
    German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany.
    Gailus-Durner, Valerie
    German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany.
    Hrabe de Angelis, Martin
    German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany.; Tech Univ Munich, Ctr Life & Food Sci Weihenstephan, Expt Genet, Neuherberg, Germany.; German Ctr Diabet Res DZD, Neuherberg, Germany.
    Rask-Andersen, Helge
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Johansson, Henrik J.
    Karolinska Inst, Dept Oncol Pathol, Sci Life Lab, Canc Prote Mass Spectrometry, Stockholm, Sweden.
    Lehtiö, Janne
    Karolinska Inst, Dept Oncol Pathol, Sci Life Lab, Canc Prote Mass Spectrometry, Stockholm, Sweden.
    He, Liqun
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Yildirim, Ali Ö.
    German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany.; Comprehensive Pneumology Center, Institute of Lung Biology and Disease, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), The German Center for Lung Research (DZL), Munich, Germany.
    Hellström, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Female mice lacking Pald1 exhibit endothelial cell apoptosis and emphysema2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, no 15453Article in journal (Refereed)
    Abstract [en]

    Paladin (Pald1, mKIAA1274 or x99384) was identified in screens for vascular-specific genes and is a putative phosphatase. Paladin has also been proposed to be involved in various biological processes such as insulin signaling, innate immunity and neural crest migration. To determine the role of paladin we have now characterized the Pald1 knock-out mouse in a broad array of behavioral, physiological and biochemical tests. Here, we show that female, but not male, Pald1 heterozygous and homozygous knock-out mice display an emphysema-like histology with increased alveolar air spaces and impaired lung function with an obstructive phenotype. In contrast to many other tissues where Pald1 is restricted to the vascular compartment, Pald1 is expressed in both the epithelial and mesenchymal compartments of the postnatal lung. However, in Pald1 knock-out females, there is a specific increase in apoptosis and proliferation of endothelial cells, but not in non-endothelial cells. This results in a transient reduction of endothelial cells in the maturing lung. Our data suggests that Pald1 is required during lung vascular development and for normal function of the developing and adult lung in a sex-specific manner. To our knowledge, this is the first report of a sex-specific effect on endothelial cell apoptosis.

  • 3. Gaengel, Konstantin
    et al.
    Niaudet, Colin
    Hagikura, Kazuhiro
    Siemsen, Barbara Lavina
    Muhl, Lars
    Hofmann, Jennifer J.
    Ebarasi, Lwaki
    Nystrom, Staffan
    Rymo, Simin
    Chen, Long Long
    Pang, Mei-Fong
    Jin, Yi
    Raschperger, Elisabeth
    Roswall, Pernilla
    Schulte, Doerte
    Benedito, Rui
    Larsson, Jimmy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Hellström, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Fuxe, Jonas
    Uhlen, Per
    Adams, Ralf
    Jakobsson, Lars
    Majumdar, Arindam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Vestweber, Dietmar
    Uv, Anne
    Betsholtz, Christer
    The Sphingosine-1-Phosphate Receptor S1PR1 Restricts Sprouting Angiogenesis by Regulating the Interplay between VE-Cadherin and VEGFR22012In: Developmental Cell, ISSN 1534-5807, E-ISSN 1878-1551, Vol. 23, no 3, p. 587-599Article in journal (Refereed)
    Abstract [en]

    Angiogenesis, the process by which new blood vessels arise from preexisting ones, is critical for embryonic development and is an integral part of many disease processes. Recent studies have provided detailed information on how angiogenic sprouts initiate, elongate, and branch, but less is known about how these processes cease. Here, we show that S1PR1, a receptor for the blood-borne bioactive lipid sphingosine-1-phosphate (S1P), is critical for inhibition of angiogenesis and acquisition of vascular stability. Loss of S1PR1 leads to increased endothelial cell sprouting and the formation of ectopic vessel branches. Conversely, S1PR1 signaling inhibits angiogenic sprouting and enhances cell-to-cell adhesion. This correlates with inhibition of vascular endothelial growth factor-A (VEGF-A)-induced signaling and stabilization of vascular endothelial (VE)-cadherin localization at endothelial junctions. Our data suggest that S1PR1 signaling acts as a vascular-intrinsic stabilization mechanism, protecting developing blood vessels against aberrant angiogenic responses.

  • 4. Haller, B K
    et al.
    Bråve, A
    Wallgard, Elisabet
    Roswall, P
    Sunkari, V G
    Mattson, U
    Hallengärd, D
    Catrina, S-B
    Hellström, Mats
    Bioinvent International, Lund, Sweden.
    Pietras, K
    Therapeutic efficacy of a DNA vaccine targeting the endothelial tip cell antigen delta-like ligand 4 in mammary carcinoma.2010In: Oncogene, ISSN 1476-5594, Vol. 29, no 30, p. 4276-86Article in journal (Refereed)
    Abstract [en]

    The Notch ligand delta-like ligand 4 (DLL4) is an essential component expressed by endothelial tip cells during angiogenic sprouting. We have described a conceptually novel therapeutic strategy for targeting tumor angiogenesis and endothelial tip cells based on DNA vaccination against DLL4. Immunization with DLL4-encoding plasmid DNA by in vivo electroporation severely retarded the growth of orthotopically implanted mammary carcinomas in mice by induction of a nonproductive angiogenic response. Mechanistically, vaccination brought about a break in tolerance against the self-antigen, DLL4, as evidenced by the production of inhibitory and inherently therapeutic antibodies against mouse DLL4. Importantly, no evidence for a delayed wound healing response, or for toxicity associated with pharmacological blockade of DLL4 signaling, was noted in mice immunized with the DLL4 vaccine. We have thus developed a well-tolerated DNA vaccination strategy targeting the endothelial tip cells and the antigen DLL4 with proven therapeutic efficacy in mouse models of mammary carcinoma; a disease that has been reported to dramatically induce the expression of DLL4. Conceivably, induction of immunity toward principal mediators of pathological angiogenesis could provide protection against recurrent malignant disease in the adjuvant setting.

  • 5. Heiss, Maximilian
    et al.
    Hellstrom, Mats
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Kalen, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    May, Tobias
    Weber, Holger
    Hecker, Markus
    Augustin, Hellmut G.
    Korff, Thomas
    Endothelial cell spheroids as a versatile tool to study angiogenesis in vitro2015In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 29, no 7, p. 3076-3084Article in journal (Refereed)
    Abstract [en]

    Given the need for robust and cost-efficient in vitro models to study angiogenesis and reproducibly analyze potential pro-and antiangiogenic compounds in preclinical studies, we developed a 3-dimensional in vitro angiogenesis assay that is based on collagen gel-embedded, size-defined spheroids generated from cultured human umbilical vein endothelial cells (HUVECs). Despite its wide distribution, limitations, sensitivity, robustness, and improvements, the capacity of this assay for functional screening purposes has not been elucidated thus far. By using time-lapse video microscopy, we show that tip cells lead the formation of capillary-like and partially lumenized sprouts originating from the spheroids. Angiogenic sprouting from spheroids generated from 5 different primary cultured human endothelial cell types was induced by physiologic concentrations of vascular endothelial cell growth factor 165. Based on this assay system, we determined the capacity of 880 approved drugs to interfere with or boost angiogenic sprouting, thereby assessing their putative angiogenesis-related side effects or novel applications. However, although this assay allowed for a rapid and reproducible determination of functional IC50 values of individual compounds, the sprouting results were partially affected by the HUVEC passage number and donor variability. To overcome this limitation, immortalized HUVECs (iHUVECs) showing a more homogenous response in terms of proliferation and sprouting over multiple population doublings were used in the course of this study. Collectively, the spheroid-based angiogenesis assay provides a sensitive and versatile tool to study the impact of pro-and antiangiogenic determinants on multiple steps of the angiogenic cascade. It is compatible with different endothelial cell types and allows use of iHUVECs to improve its overall robustness.

  • 6.
    Hellström, Mats
    et al.
    AngioGenetics Sweden AB och Karolinska Institutet, Institutionen för medicinsk biokemi och biofysik.
    Phng, Li-Kun
    Hofmann, Jennifer J
    Wallgard, Elisabet
    AngioGenetics Sweden AB och Karolinska Institutet, Institutionen för medicinsk biokemi och biofysik.
    Coultas, Leigh
    Lindblom, Per
    Alva, Jackelyn
    Nilsson, Ann-Katrin
    Karlsson, Linda
    Gaiano, Nicholas
    Yoon, Keejung
    Rossant, Janet
    Iruela-Arispe, M Luisa
    Kalén, Mattias
    Gerhardt, Holger
    Betsholtz, Christer
    Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis.2007In: Nature, ISSN 1476-4687, Vol. 445, no 7129, p. 776-80Article in journal (Refereed)
    Abstract [en]

    In sprouting angiogenesis, specialized endothelial tip cells lead the outgrowth of blood-vessel sprouts towards gradients of vascular endothelial growth factor (VEGF)-A. VEGF-A is also essential for the induction of endothelial tip cells, but it is not known how single tip cells are selected to lead each vessel sprout, and how tip-cell numbers are determined. Here we present evidence that delta-like 4 (Dll4)-Notch1 signalling regulates the formation of appropriate numbers of tip cells to control vessel sprouting and branching in the mouse retina. We show that inhibition of Notch signalling using gamma-secretase inhibitors, genetic inactivation of one allele of the endothelial Notch ligand Dll4, or endothelial-specific genetic deletion of Notch1, all promote increased numbers of tip cells. Conversely, activation of Notch by a soluble jagged1 peptide leads to fewer tip cells and vessel branches. Dll4 and reporters of Notch signalling are distributed in a mosaic pattern among endothelial cells of actively sprouting retinal vessels. At this location, Notch1-deleted endothelial cells preferentially assume tip-cell characteristics. Together, our results suggest that Dll4-Notch1 signalling between the endothelial cells within the angiogenic sprout serves to restrict tip-cell formation in response to VEGF, thereby establishing the adequate ratio between tip and stalk cells required for correct sprouting and branching patterns. This model offers an explanation for the dose-dependency and haploinsufficiency of the Dll4 gene, and indicates that modulators of Dll4 or Notch signalling, such as gamma-secretase inhibitors developed for Alzheimer's disease, might find usage as pharmacological regulators of angiogenesis.

  • 7.
    Hjelmqvist, Daisy
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Hellström, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lau, Joey
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Improving Pancreatic Islet Engraftment after Islet Transplantation through Administration of Gamma-Secretase Inhibitor DAPT2014In: Journal of endocrinology and diabetes mellitus, ISSN 2310-9971, Vol. 2, p. 65-69Article in journal (Refereed)
    Abstract [en]

    Abstract: Rapid and effective revascularization of transplanted pancreatic islets is vital for the survival and function of the islet graft. Insufficient vascularization after islet transplantation may be one causative factor to the failure of islet grafts in clinical transplantation. The aim of this study was to investigate if N-{N-[2-(3,5-Difluorophenyl)acetyl]-(S)-alanyl}- (S)-phenylglycine- tert-butyl ester (DAPT) administration can improve engraftment of transplanted islets. DAPT is a dipeptidic gamma-secretase inhibitor which inhibits Notch signaling. Notch signaling is involved in angiogenesis and inhibition may result in excessive formation of new blood vessels. Excessive vasculature may be beneficial in the immediate posttransplantation period since the transplanted islets are dependent on diffusion of oxygen and nutrients before revascularization. Islets isolated from C57BL/6 mice were transplanted beneath the renal capsule of C57BL/6 mice. After islet transplantation DAPT or vehicle was administered subcutaneously for three days. Mice treated with DAPT had an increased vascular density when compared to control mice two days and one month posttransplantation. Moreover, mice treated with DAPT showed 54±8.2 % functional blood vessels compared to 40±6.7 % in control mice two days posttransplantation. After one month, the fraction of functional blood vessels increased to 86±2.8 % in DAPT treated mice compared to 61±9.4 % in control mice. Our findings demonstrated that administration of DAPT may be a feasible strategy to improve engraftment of transplanted islets.

  • 8.
    Kalén, Mattias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Heikura, Tommi
    Karvinen, Henna
    Nitzsche, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Weber, Holger
    Esser, Norbert
    Yla-Herttuala, Seppo
    Hellström, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Gamma-Secretase Inhibitor Treatment Promotes VEGF-A-Driven Blood Vessel Growth and Vascular Leakage but Disrupts Neovascular Perfusion2011In: PLOS ONE, ISSN 1932-6203, Vol. 6, no 4, p. e18709-Article in journal (Refereed)
    Abstract [en]

    The Notch signaling pathway is essential for normal development due to its role in control of cell differentiation, proliferation and survival. It is also critically involved in tumorigenesis and cancer progression. A key enzyme in the activation of Notch signaling is the gamma-secretase protein complex and therefore, gamma-secretase inhibitors (GSIs)originally developed for Alzheimer's disease-are now being evaluated in clinical trials for human malignancies. It is also clear that Notch plays an important role in angiogenesis driven by Vascular Endothelial Growth Factor A (VEGF-A)-a process instrumental for tumor growth and metastasis. The effect of GSIs on tumor vasculature has not been conclusively determined. Here we report that Compound X (CX), a GSI previously reported to potently inhibit Notch signaling in vitro and in vivo, promotes angiogenic sprouting in vitro and during developmental angiogenesis in mice. Furthermore, CX treatment suppresses tumor growth in a mouse model of renal carcinoma, leads to the formation of abnormal vessels and an increased tumor vascular density. Using a rabbit model of VEGF-A-driven angiogenesis in skeletal muscle, we demonstrate that CX treatment promotes abnormal blood vessel growth characterized by vessel occlusion, disrupted blood flow, and increased vascular leakage. Based on these findings, we propose a model for how GSIs and other Notch inhibitors disrupt tumor blood vessel perfusion, which might be useful for understanding this new class of anti-cancer agents.

  • 9. Kalén, Mattias
    et al.
    Wallgard, Elisabet
    Karolinska Institutet, Institutionen för medicinsk biokemi och biofysik.
    Asker, Noomi
    Nasevicius, Aidas
    Athley, Elisabet
    Billgren, Erik
    Larson, Jon D
    Wadman, Shannon A
    Norseng, Elizabeth
    Clark, Karl J
    He, Liqun
    Karlsson-Lindahl, Linda
    Häger, Ann-Katrin
    Weber, Holger
    Augustin, Hellmut
    Samuelsson, Tore
    Kemmet, Chelsy K
    Utesch, Carly M
    Essner, Jeffrey J
    Hackett, Perry B
    Hellström, Mats
    Karolinska Institutet, Institutionen för medicinsk biokemi och biofysik.
    Combination of reverse and chemical genetic screens reveals angiogenesis inhibitors and targets.2009In: Chemistry and Biology, ISSN 1074-5521, E-ISSN 1879-1301, Vol. 16, no 4, p. 432-41Article in journal (Refereed)
    Abstract [en]

    We combined reverse and chemical genetics to identify targets and compounds modulating blood vessel development. Through transcript profiling in mice, we identified 150 potentially druggable microvessel-enriched gene products. Orthologs of 50 of these were knocked down in a reverse genetic screen in zebrafish, demonstrating that 16 were necessary for developmental angiogenesis. In parallel, 1280 pharmacologically active compounds were screened in a human cell-based assay, identifying 28 compounds selectively inhibiting endothelial sprouting. Several links were revealed between the results of the reverse and chemical genetic screens, including the serine/threonine (S/T) phosphatases ppp1ca, ppp1cc, and ppp4c and an inhibitor of this gene family; Endothall. Our results suggest that the combination of reverse and chemical genetic screens, in vertebrates, is an efficient strategy for the identification of drug targets and compounds that modulate complex biological systems, such as angiogenesis.

  • 10.
    Kundu, Snehangshu
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ali, Muhammad Akhtar
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Handin, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Padhan, Narendra
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Larsson, Jimmy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Karoutsou, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ban, Kenneth
    Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Biochem, 8 Med Dr,02-06, Singapore 117597, Singapore.;ASTAR, Inst Mol & Cell Biol, Singapore 138673, Singapore..
    Wisniewski, Jacek R.
    Max Planck Inst Biochem, Dept Prote & Signal Transduct, Biochem Prote Grp, D-82152 Martinsried, Germany..
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    He, Liqun
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab. Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin Neurological Institute, Key Laboratory of Post-Neuroinjury Neuro-Repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin, China.
    Hellström, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sjöblom, Tobias
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Linking FOXO3, NCOA3, and TCF7L2 to Ras pathway phenotypes through a genome-wide forward genetic screen in human colorectal cancer cells2018In: Genome Medicine, ISSN 1756-994X, E-ISSN 1756-994X, Vol. 10, article id 2Article in journal (Refereed)
    Abstract [en]

    Background:

    The Ras pathway genes KRAS, BRAF, or ERBBs have somatic mutations in similar to 60% of human colorectal carcinomas. At present, it is unknown whether the remaining cases lack mutations activating the Ras pathway or whether they have acquired mutations in genes hitherto unknown to belong to the pathway.

    Methods:

    To address the second possibility and extend the compendium of Ras pathway genes, we used genome-wide transposon mutagenesis of two human colorectal cancer cell systems deprived of their activating KRAS or BRAF allele to identify genes enabling growth in low glucose, a Ras pathway phenotype, when targeted.

    Results:

    Of the 163 recurrently targeted genes in the two different genetic backgrounds, one-third were known cancer genes and one-fifth had links to the EGFR/Ras/MAPK pathway. When compared to cancer genome sequencing datasets, nine genes also mutated in human colorectal cancers were identified. Among these, stable knockdown of FOXO3, NCOA3, and TCF7L2 restored growth in low glucose but reduced MEK/MAPK phosphorylation, reduced anchorage-independent growth, and modulated expressions of GLUT1 and Ras pathway related proteins. Knockdown of NCOA3 and FOXO3 significantly decreased the sensitivity to cetuximab of KRAS mutant but not wild-type cells.

    Conclusions:

    This work establishes a proof-of-concept that human cell-based genome-wide forward genetic screens can assign genes to pathways with clinical importance in human colorectal cancer.

  • 11.
    Mansouri, Larry
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Sutton, Lesley-Ann
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Ljungström, Viktor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Bondza, Sina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Arngården, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Bhoi, Sujata
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Larsson, Jimmy
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Cortese, Diego
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Kalushkova, Antonia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Gunnarsson, Rebeqa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Young, Emma
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Falk-Sörqvist, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Plevova, Karla
    Muggen, Alice
    Yan, Xiao-Jie
    Sander, Birgitta
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Smedby, Karin E.
    Juliusson, Gunnar
    Belessi, Chrysoula
    Chiorazzi, Nicholas
    Strefford, Jonathan C.
    Langerak, Anton W.
    Pospisilova, Sarka
    Davi, Frederic
    Hellström, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Wiklund, Helena Jernberg
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Ghia, Paolo
    Söderberg, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Stamatopoulos, Kostas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Nilsson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Recurrent Mutations within the Nfkbie gene: A Novel Mechanism for NF-kappa B Deregulation in Aggressive Chronic Lymphocytic Leukemia2014In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 124, no 21Article in journal (Other academic)
  • 12.
    Mansouri, Larry
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sutton, Lesley-Ann
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Ljungström, Viktor
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Bondza, Sina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Arngården, Linda
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Bhoi, Sujata
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Larsson, Jimmy
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Cortese, Diego
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Kalushkova, Antonia
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Plevova, Karla
    Central European Institute of Technology, Masaryk University & University Hospital Brno, Brno, Czech Republic.
    Young, Emma
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Gunnarsson, Rebeqa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Falk Sörqvist, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lönn, Peter
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Muggen, Alice F.
    Department of Immunology, Erasmus MC, University Medical Center Rotterdam, the Netherlands.
    Yan, Xiao-Jie
    The Karches Center for Chronic Lymphocytic Leukemia Research, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America, .
    Sander, Birgitta
    Department of Laboratory Medicine, Division of Pathology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
    Enblad, Gunilla
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Smedby, Karin E.
    Department of Medicine, Clinical Epidemiology Unit, Karolinska Institutet, Stockholm, Sweden.
    Juliusson, Gunnar
    Department of Laboratory Medicine, Stem Cell Center, Hematology and Transplantation, Lund University, Lund, Sweden.
    Belessi, Chrysoula
    Hematology Department, General Hospital of Nikea, Piraeus, Greece.
    Rung, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Chiorazzi, Nicholas
    The Karches Center for Chronic Lymphocytic Leukemia Research, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America.
    Strefford, Jonathan C.
    Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
    Langerak, Anton W.
    Department of Immunology, Erasmus MC, University Medical Center Rotterdam, the Netherlands.
    Pospisilova, Sarka
    Central European Institute of Technology, Masaryk University & University Hospital Brno, Brno, Czech Republic.
    Davi, Frederic
    AP-HP, Hôpital Pitié-Salpêtrière, Department of Hematology, and Sorbonne Universités, UPMC Univ Paris 06, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France.
    Hellström, Mats
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Jernberg Wiklund, Helena
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Ghia, Paolo
    Division of Experimental Oncology, Department of Onco-Haematology, IRCCS Istituto Scientifico San Raffaele, Fondazione Centro San Raffaele, Università Vita-Salute San Raffaele, Milan, Italy.
    Söderberg, Ola
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Stamatopoulos, Kostas
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. nstitute of Applied Biosciences, Center for Research and Technology, Thessaloniki, Greece.
    Nilsson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden.
    Rosenquist Brandell, Richard
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Functional loss of IκBε leads to NF-κB deregulation in aggressive chronic lymphocytic leukemia2015In: Journal of Experimental Medicine, ISSN 0022-1007, E-ISSN 1540-9538, Vol. 212, no 6, p. 833-843Article in journal (Refereed)
    Abstract [en]

    NF-κB is constitutively activated in chronic lymphocytic leukemia (CLL); however, the implicated molecular mechanisms remain largely unknown. Thus, we performed targeted deep sequencing of 18 core complex genes within the NF-κB pathway in a discovery and validation CLL cohort totaling 315 cases. The most frequently mutated gene was NFKBIE (21/315 cases; 7%), which encodes IκBε, a negative regulator of NF-κB in normal B cells. Strikingly, 13 of these cases carried an identical 4-bp frameshift deletion, resulting in a truncated protein. Screening of an additional 377 CLL cases revealed that NFKBIE aberrations predominated in poor-prognostic patients and were associated with inferior outcome. Minor subclones and/or clonal evolution were also observed, thus potentially linking this recurrent event to disease progression. Compared with wild-type patients, NFKBIE-deleted cases showed reduced IκBε protein levels and decreased p65 inhibition, along with increased phosphorylation and nuclear translocation of p65. Considering the central role of B cell receptor (BcR) signaling in CLL pathobiology, it is notable that IκBε loss was enriched in aggressive cases with distinctive stereotyped BcR, likely contributing to their poor prognosis, and leading to an altered response to BcR inhibitors. Because NFKBIE deletions were observed in several other B cell lymphomas, our findings suggest a novel common mechanism of NF-κB deregulation during lymphomagenesis.

  • 13.
    Nitzsche, Anja
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Testini, Chiara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Ekvärn, Elisabet
    Larsson, Jimmy
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Bentley, Katie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Philippides, Andrew
    Roche, Francis P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Egaña, Isabel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Smith, Ross
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Hellberg, Carina
    Ballmer-Hofer, Kurt
    Hellström, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Paladin (Pald1) regulates endothelial sprouting, VE-cadherin junction stability and vascular permeabilityManuscript (preprint) (Other academic)
  • 14.
    Pandzic, Tatjana
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Larsson, Jimmy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    He, Liqun
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Kundu, Snehangshu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ban, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab. NUS, Yong Loo Lin Sch Med, A STAR, Dept Biochem,Inst Mol & Cell Biol, Singapore, Singapore..
    Ali, Muhammad Akhtar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hellström, Anders R.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Schuh, Anna
    Univ Oxford, Radcliffe Dept Med, Oxford, England..
    Clifford, Ruth
    Univ Oxford, Radcliffe Dept Med, Oxford, England..
    Blakemore, Stuart J.
    Univ Southampton, Canc Sci, Fac Med, Southampton, Hants, England..
    Strefford, Jonathan C.
    Univ Southampton, Canc Sci, Fac Med, Southampton, Hants, England..
    Baumann, Tycho
    Univ Southampton, Canc Sci, Fac Med, Southampton, Hants, England..
    Lopez-Guillermo, Armando
    Hosp Clin Barcelona, IDIBAPS, Serv Hematol, Barcelona, Spain..
    Campo, Elias
    Univ Barcelona, IDIBAPS, Hosp Clin, Unitat Hematol, Barcelona, Spain..
    Ljungström, Viktor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mansouri, Larry
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sjöblom, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hellström, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Transposon Mutagenesis Reveals Fludarabine Resistance Mechanisms in Chronic Lymphocytic Leukemia2016In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 22, no 24, p. 6217-6227Article in journal (Refereed)
    Abstract [en]

    Purpose: To identify resistance mechanisms for the chemotherapeutic drug fludarabine in chronic lymphocytic leukemia (CLL), as innate and acquired resistance to fludarabine-based chemotherapy represents a major challenge for long-term disease control. Experimental Design: We used piggyBac transposon-mediated mutagenesis, combined with next-generation sequencing, to identify genes that confer resistance to fludarabine in a human CLL cell line. Results: In total, this screen identified 782 genes with transposon integrations in fludarabine-resistant pools of cells. One of the identified genes is a known resistance mediator DCK (deoxycytidine kinase), which encodes an enzyme that is essential for the phosphorylation of the prodrug to the active metabolite. BMP2K, a gene not previously linked to CLL, was also identified as a modulator of response to fludarabine. In addition, 10 of 782 transposon-targeted genes had previously been implicated in treatment resistance based on somatic mutations seen in patients refractory to fludarabine-based therapy. Functional characterization of these genes supported a significant role for ARID5B and BRAF in fludarabine sensitivity. Finally, pathway analysis of transposon-targeted genes and RNA-seq profiling of fludarabine-resistant cells suggested deregulated MAPK signaling as involved in mediating drug resistance in CLL. Conclusions: To our knowledge, this is the first forward genetic screen for chemotherapy resistance in CLL. The screen pinpointed novel genes and pathways involved in fludarabine resistance along with previously known resistance mechanisms. Transposon screens can therefore aid interpretation of cancer genome sequencing data in the identification of genes modifying sensitivity to chemotherapy.

  • 15.
    Pandzic, Tatjana
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Rendo, Verónica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lim, Jinyeong
    Department of Cancer Biomedical Science, National Cancer Center Graduate School of Cancer Science and Policy, Goyangsi, Republic of Korea.
    Larsson, Chatarina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Larsson, Jimmy
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Systems Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Stoimenov, Ivaylo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Kundu, Snehangshu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ali, Muhammad Akhtar
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Hellström, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    He, Liqun
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lindroth, Anders M.
    Department of Cancer Biomedical Science, National Cancer Center Graduate School of Cancer Science and Policy, Goyangsi, Republic of Korea.
    Sjöblom, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Somatic PRDM2 c.4467delA mutations in colorectal cancers control histone methylation and tumor growth2017In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 58, p. 98646-98659Article in journal (Refereed)
    Abstract [en]

    The chromatin modifier PRDM2/RIZ1 is inactivated by mutation in several forms of cancer and is a putative tumor suppressor gene. Frameshift mutations in the C-terminal region of PRDM2, affecting (A)8 or (A)9 repeats within exon 8, are found in one third of colorectal cancers with microsatellite instability, but the contribution of these mutations to colorectal tumorigenesis is unknown. To model somatic mutations in microsatellite unstable tumors, we devised a general approach to perform genome editing while stabilizing the mutated nucleotide repeat. We then engineered isogenic cell systems where the PRDM2 c.4467delA mutation in human HCT116 colorectal cancer cells was corrected to wild-type by genome editing. Restored PRDM2 increased global histone 3 lysine 9 dimethylation and reduced migration, anchorage-independent growth and tumor growth in vivo. Gene set enrichment analysis revealed regulation of several hallmark cancer pathways, particularly of epithelial-to-mesenchymal transition (EMT), with VIM being the most significantly regulated gene. These observations provide direct evidence that PRDM2 c.4467delA is a driver mutation in colorectal cancer and confirms PRDM2 as a cancer gene, pointing to regulation of EMT as a central aspect of its tumor suppressive action.

  • 16. Tammela, Tuomas
    et al.
    Zarkada, Georgia
    Wallgard, Elisabet
    Karolinska Institutet, Institutionen för medicinsk biokemi och biofysik.
    Murtomäki, Aino
    Suchting, Steven
    Wirzenius, Maria
    Waltari, Marika
    Hellström, Mats
    Karolinska Institutet, Institutionen för medicinsk biokemi och biofysik.
    Schomber, Tibor
    Peltonen, Reetta
    Freitas, Catarina
    Duarte, Antonio
    Isoniemi, Helena
    Laakkonen, Pirjo
    Christofori, Gerhard
    Ylä-Herttuala, Seppo
    Shibuya, Masabumi
    Pytowski, Bronislaw
    Eichmann, Anne
    Betsholtz, Christer
    Alitalo, Kari
    Blocking VEGFR-3 suppresses angiogenic sprouting and vascular network formation.2008In: Nature, ISSN 1476-4687, Vol. 454, no 7204, p. 656-60Article in journal (Refereed)
    Abstract [en]

    Angiogenesis, the growth of new blood vessels from pre-existing vasculature, is a key process in several pathological conditions, including tumour growth and age-related macular degeneration. Vascular endothelial growth factors (VEGFs) stimulate angiogenesis and lymphangiogenesis by activating VEGF receptor (VEGFR) tyrosine kinases in endothelial cells. VEGFR-3 (also known as FLT-4) is present in all endothelia during development, and in the adult it becomes restricted to the lymphatic endothelium. However, VEGFR-3 is upregulated in the microvasculature of tumours and wounds. Here we demonstrate that VEGFR-3 is highly expressed in angiogenic sprouts, and genetic targeting of VEGFR-3 or blocking of VEGFR-3 signalling with monoclonal antibodies results in decreased sprouting, vascular density, vessel branching and endothelial cell proliferation in mouse angiogenesis models. Stimulation of VEGFR-3 augmented VEGF-induced angiogenesis and sustained angiogenesis even in the presence of VEGFR-2 (also known as KDR or FLK-1) inhibitors, whereas antibodies against VEGFR-3 and VEGFR-2 in combination resulted in additive inhibition of angiogenesis and tumour growth. Furthermore, genetic or pharmacological disruption of the Notch signalling pathway led to widespread endothelial VEGFR-3 expression and excessive sprouting, which was inhibited by blocking VEGFR-3 signals. Our results implicate VEGFR-3 as a regulator of vascular network formation. Targeting VEGFR-3 may provide additional efficacy for anti-angiogenic therapies, especially towards vessels that are resistant to VEGF or VEGFR-2 inhibitors.

  • 17.
    Testini, Chiara
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Smith, Ross O.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Jin, Yi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Martinsson, Pernilla
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Sun, Ying
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hedlund, Marie
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Sainz-Jaspeado, Miguel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Shibuya, Masabumi
    Jobu Univ, Inst Physiol & Med, Takasaki, Gunma, Japan.
    Hellström, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Claesson-Welsh, Lena
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Myc-dependent endothelial proliferation is controlled by phosphotyrosine 1212 in VEGF receptor-22019In: EMBO Reports, ISSN 1469-221X, E-ISSN 1469-3178, Vol. 20, no 11, article id e47845Article in journal (Refereed)
    Abstract [en]

    Exaggerated signaling by vascular endothelial growth factor (VEGF)-A and its receptor, VEGFR2, in pathologies results in poor vessel function. Still, pharmacological suppression of VEGFA/VEGFR2 may aggravate disease. Delineating VEGFR2 signaling in vivo provides strategies for suppression of specific VEGFR2-induced pathways. Three VEGFR2 tyrosine residues (Y949, Y1212, and Y1173) induce downstream signaling. Here, we show that knock-in of phenylalanine to create VEGFR2 Y1212F in C57Bl/6 and FVB mouse strains leads to loss of growth factor receptor-bound protein 2- and phosphoinositide 3 '-kinase (PI3K)p85 signaling. C57Bl/6 Vegfr2(Y1212F/Y1212F) show reduced embryonic endothelial cell (EC) proliferation and partial lethality. FVB Vegfr2(Y1212F/Y1212F) show reduced postnatal EC proliferation. Reduced EC proliferation in Vegfr2(Y1212F/Y1212F) explants is rescued by c-Myc overexpression. We conclude that VEGFR2 Y1212 signaling induces activation of extracellular-signal-regulated kinase (ERK)1/2 and Akt pathways required for c-Myc-dependent gene regulation, endothelial proliferation, and vessel stability.

  • 18.
    Wallgard, Elisabet
    et al.
    Karolinska Institutet, Institutionen för medicinsk biokemi och biofysik.
    Larsson, Erik
    He, Liqun
    Hellström, Mats
    Karolinska Institutet, Institutionen för medicinsk biokemi och biofysik.
    Armulik, Annika
    Nisancioglu, Maya H
    Genove, Guillem
    Lindahl, Per
    Betsholtz, Christer
    Identification of a core set of 58 gene transcripts with broad and specific expression in the microvasculature.2008In: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 28, no 8, p. 1469-76Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Pathological angiogenesis is an integral component of many diseases. Antiangiogenesis and vascular targeting are therefore promising new therapeutic principles. However, few endothelial-specific putative drug targets have been identified, and information is still limited about endothelial-specific molecular processes. Here we aimed at determining the endothelial cell-specific core transcriptome in vivo.

    METHODS AND RESULTS: Analysis of publicly available microarray data identified a mixed vascular/lung cluster of 132 genes that correlated with known endothelial markers. Filtering against kidney glomerular/nonglomerular and brain vascular/nonvascular microarray profiles separated contaminating lung markers, leaving 58 genes with broad and specific microvascular expression. More than half of these have not previously been linked to endothelial functions or studied in detail before. The endothelial cell-specific expression of a selected subset of these, Eltd1, Gpr116, Ramp2, Slc9a3r2, Slc43a3, Rasip1, and NM_023516, was confirmed by real-time quantitative polymerase chain reaction and/or immunohistochemistry.

    CONCLUSIONS: We have used a combination of publicly available and own microarray data to identify 58 gene transcripts with broad yet specific expression in microvascular endothelium. Most of these have unknown functions, but many of them are predicted to be cell surface expressed or implicated in cell signaling processes and should therefore be explored as putative microvascular drug targets.

  • 19.
    Wallgard, Elisabet
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Nitzsche, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Larsson, Jimmy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Guo, Xiaoyuan
    Dieterich, Lothar C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Dimberg, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Olofsson, Tommie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Pontén, Fredrik C
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Maekinen, Taija
    Kalen, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Hellström, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Paladin (X99384) is expressed in the vasculature and shifts from endothelial to vascular smooth muscle cells during mouse development2012In: Developmental Dynamics, ISSN 1058-8388, E-ISSN 1097-0177, Vol. 241, no 4, p. 770-786Article in journal (Refereed)
    Abstract [en]

    Background: Angiogenesis is implicated in many pathological conditions. The role of the proteins involved remains largely unknown, and few vascular-specific drug targets have been discovered. Previously, in a screen for angiogenesis regulators, we identified Paladin (mouse: X99384, human: KIAA1274), a protein containing predicted S/T/Y phosphatase domains.

    Results: We present a mouse knockout allele for Paladin with a beta-galactosidase reporter, which in combination with Paladin antibodies demonstrate that Paladin is expressed in the vasculature. During mouse embryogenesis, Paladin is primarily expressed in capillary and venous endothelial cells. In adult mice Paladin is predominantly expressed in arterial pericytes and vascular smooth muscle cells. Paladin also displays vascular-restricted expression in human brain, astrocytomas, and glioblastomas.

    Conclusions: Paladin, a novel putative phosphatase, displays a dynamic expression pattern in the vasculature. During embryonic stages it is broadly expressed in endothelial cells, while in the adult it is selectively expressed in arterial smooth muscle cells.

1 - 19 of 19
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