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Johansson, Staffan
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Publications (10 of 41) Show all publications
Lugano, R., Vemuri, K., Yu, D., Bergqvist, M., Smits, A., Essand, M., . . . Dimberg, A. (2018). CD93 promotes β1 integrin activation and fibronectin fibrillogenesis during tumor angiogenesis.. Journal of Clinical Investigation, 128(8), 3280-3297
Open this publication in new window or tab >>CD93 promotes β1 integrin activation and fibronectin fibrillogenesis during tumor angiogenesis.
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2018 (English)In: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 128, no 8, p. 3280-3297Article in journal (Refereed) Published
Abstract [en]

Tumor angiogenesis occurs through regulation of genes that orchestrate endothelial sprouting and vessel maturation, including deposition of a vessel-associated extracellular matrix. CD93 is a transmembrane receptor that is up-regulated in tumor vessels in many cancers, including high-grade glioma. Here, we demonstrate that CD93 regulates integrin-β1-signaling and organization of fibronectin fibrillogenesis during tumor vascularization. In endothelial cells and mouse retina, CD93 was found to be expressed in endothelial filopodia and to promote filopodia formation. The CD93 localization to endothelial filopodia was stabilized by interaction with multimerin-2 (MMRN2), which inhibited its proteolytical cleavage. The CD93-MMRN2 complex was required for activation of integrin-β1, phosphorylation of focal adhesion kinase (FAK) and fibronectin fibrillogenesis in endothelial cells. Consequently, tumor vessels in gliomas implanted orthotopically in CD93-deficient mice showed diminished activation of integrin-β1 and lacked organization of fibronectin into fibrillar structures. These findings demonstrate a key role of CD93 in vascular maturation and organization of the extracellular matrix in tumors, identifying it as a potential target for therapy.

Keywords
Brain cancer, Fibronectin, Oncology, Vascular Biology, endothelial cells
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-350902 (URN)10.1172/JCI97459 (DOI)000440461500015 ()29763414 (PubMedID)
Funder
Swedish Cancer Society, CAN 2014/832Swedish Cancer Society, CAN 2017/502Swedish Cancer Society, CAN 2015/1216Swedish Childhood Cancer Foundation, PR2015-0133Swedish Childhood Cancer Foundation, NCP2015-0075Swedish Research Council, 2016-02495
Available from: 2018-05-17 Created: 2018-05-17 Last updated: 2018-11-08Bibliographically approved
Gupta, D. K., Kamranvar, S. A., Du, J., Lu, L. & Johansson, S. (2018). Fate of bi-nucleated cells: the role of septin and Ras.
Open this publication in new window or tab >>Fate of bi-nucleated cells: the role of septin and Ras
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2018 (English)Manuscript (preprint) (Other academic)
Abstract [en]

Integrin-mediated adhesion is required to complete cytokinesis, and failure in the process can generate tetraploid cells, which are potentially oncogenic. The effect of cell detachment on the cytokinesis process and on the following cell cycle was analyzed in the non-transformed human fibroblast cell line BJ and in BJ cells expressing SV40 LT (BJ-LT) +/- an oncogenic Ras mutant. In non-adherent BJ and BJ-LT cells, ALIX could not be recruited to the midbody (MB) and cytokinetic abscission did not occur. Based on the results from several approaches, this block was concluded to be overcome in the detached BJ-LT-Ras cells. Non-adherent BJ and BJ-LT cells maintained the septin-associated intercellular bridge (ICB) formed by cleavage furrow ingression, for more than 24 hours. After re-adhesion to fibronectin most such cells divided by cytofission due to tension exerted on the narrow bridge, while a minor fraction of the cell population instead became bi-nucleated because of regression of the intercellular bridge. Adherent bi-nucleated BJ-LT cells progressed through the cell cycle and at mitosis they divided into two mono-nucleated (4N) cells, while adherent bi-nucleated BJ cells were arrested in the G1 phase and became senescent. Thus, p53-dependent mechanism(s) prevented the formation of tetraploid cells from non-transformed bi-nucleated cells. The two centrosomes in the adherent bi-nucleated cells rapidly fused, indicating that p53 was activated via the PIDDosome mechanism. The results show that several mechanisms contribute to prevent detached normal cells from generating tumor-causing tetraploid cells, and that expression of an activating Ras mutation can promote cytokinesis in detached tumor cells. 

National Category
Cell Biology
Identifiers
urn:nbn:se:uu:diva-368333 (URN)
Available from: 2018-12-04 Created: 2018-12-04 Last updated: 2018-12-04
Gupta, D. K., Du, J., Kamranvar, S. A. & Johansson, S. (2018). Tension-induced cytokinetic abscission in human fibroblasts. OncoTarget
Open this publication in new window or tab >>Tension-induced cytokinetic abscission in human fibroblasts
2018 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553Article in journal, News item (Other academic) Published
National Category
Cell Biology
Identifiers
urn:nbn:se:uu:diva-368349 (URN)
Available from: 2018-12-04 Created: 2018-12-04 Last updated: 2018-12-06
Sandberg, M., Johansson, S., Sagulin, L., Jansson, L. & Johansson, S. (2017). Scavenging Endothelium of Pancreatic Islets Differential Expression of Stabilin-1 and Stabilin-2 in Mice and Humans [Letter to the editor]. Pancreas, 46(1), E4-E5
Open this publication in new window or tab >>Scavenging Endothelium of Pancreatic Islets Differential Expression of Stabilin-1 and Stabilin-2 in Mice and Humans
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2017 (English)In: Pancreas, ISSN 0885-3177, E-ISSN 1536-4828, Vol. 46, no 1, p. E4-E5Article in journal, Letter (Other academic) Published
Place, publisher, year, edition, pages
LIPPINCOTT WILLIAMS & WILKINS, 2017
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-321001 (URN)10.1097/MPA.0000000000000709 (DOI)000397644300005 ()27977633 (PubMedID)
Funder
Swedish Research Council, 521-2011-3777, 7147EXODIAB - Excellence of Diabetes Research in SwedenSwedish Diabetes Association
Available from: 2017-04-28 Created: 2017-04-28 Last updated: 2017-04-28Bibliographically approved
Hildebrand, S., Hultin, S., Subramani, A., Petropoulos, S., Zhang, Y., Cao, X., . . . Holmgren, L. (2017). The E-cadherin/AmotL2 complex organizes actin filaments required for epithelial hexagonal packing and blastocyst hatching. Scientific Reports, 7(1), Article ID 9540.
Open this publication in new window or tab >>The E-cadherin/AmotL2 complex organizes actin filaments required for epithelial hexagonal packing and blastocyst hatching
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2017 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, no 1, article id 9540Article in journal (Refereed) Published
Abstract [en]

Epithelial cells connect via cell-cell junctions to form sheets of cells with separate cellular compartments. These cellular connections are essential for the generation of cellular forms and shapes consistent with organ function. Tissue modulation is dependent on the fine-tuning of mechanical forces that are transmitted in part through the actin connection to E-cadherin as well as other components in the adherens junctions. In this report we show that p100 amotL2 forms a complex with E-cadherin that associates with radial actin filaments connecting cells over multiple layers. Genetic inactivation or depletion of amotL2 in epithelial cells in vitro or zebrafish and mouse in vivo, resulted in the loss of contractile actin filaments and perturbed epithelial packing geometry. We further showed that AMOTL2 mRNA and protein was expressed in the trophectoderm of human and mouse blastocysts. Genetic inactivation of amotL2 did not affect cellular differentiation but blocked hatching of the blastocysts from the zona pellucida. These results were mimicked by treatment with the myosin II inhibitor blebbistatin. We propose that the tension generated by the E-cadherin/AmotL2/actin filaments plays a crucial role in developmental processes such as epithelial geometrical packing as well as generation of forces required for blastocyst hatching.

National Category
Cell Biology
Identifiers
urn:nbn:se:uu:diva-339873 (URN)10.1038/s41598-017-10102-w (DOI)000408449000019 ()28842668 (PubMedID)
Available from: 2018-01-23 Created: 2018-01-23 Last updated: 2018-04-04Bibliographically approved
Riaz, A., Huang, Y. & Johansson, S. (2016). G-Protein-Coupled Lysophosphatidic Acid Receptors and Their Regulation of AKT Signaling. International Journal of Molecular Sciences, 17(2)
Open this publication in new window or tab >>G-Protein-Coupled Lysophosphatidic Acid Receptors and Their Regulation of AKT Signaling
2016 (English)In: International Journal of Molecular Sciences, ISSN 1422-0067, E-ISSN 1422-0067, Vol. 17, no 2Article, review/survey (Refereed) Published
Abstract [en]

A hallmark of G-protein-coupled receptors (GPCRs) is their ability to recognize and respond to chemically diverse ligands. Lysophospholipids constitute a relatively recent addition to these ligands and carry out their biological functions by activating G-proteins coupled to a large family of cell-surface receptors. This review aims to highlight salient features of cell signaling by one class of these receptors, known as lysophosphatidic acid (LPA) receptors, in the context of phosphatidylinositol 3-kinase (PI3K)-AKT pathway activation. LPA moieties efficiently activate AKT phosphorylation and activation in a multitude of cell types. The interplay between LPA, its receptors, the associated Gi/o subunits, PI3K and AKT contributes to the regulation of cell survival, migration, proliferation and confers chemotherapy-resistance in certain cancers. However, detailed information on the regulation of PI3K-AKT signals induced by LPA receptors is missing from the literature. Here, some urgent issues for investigation are highlighted.

Keywords
G-protein coupled receptors (GPCR), lysophosphatidic acid (LPA), PI3K, AKT
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-298961 (URN)10.3390/ijms17020215 (DOI)000371830800097 ()
Funder
Swedish Cancer Society
Available from: 2016-07-13 Created: 2016-07-12 Last updated: 2017-11-28Bibliographically approved
Wu, C., Cao, X., Yu, D., Huijbers, E. J. M., Essand, M., Akusjärvi, G., . . . Svensson, C. (2016). HAdV-2-suppressed growth of SV40 T antigen-transformed mouse mammary epithelial cell-induced tumours in SCID mice. Virology, 489, 44-50
Open this publication in new window or tab >>HAdV-2-suppressed growth of SV40 T antigen-transformed mouse mammary epithelial cell-induced tumours in SCID mice
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2016 (English)In: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 489, p. 44-50Article in journal (Refereed) Published
Abstract [en]

Human adenovirus (HAdV) vectors are promising tools for cancer therapy, but the shortage of efficient animal models for productive HAdV infections has restricted the evaluation of systemic effects to mainly immunodeficient mice. Previously, we reported a highly efficient replication of HAdV-2 in a non-tumorigenic mouse mammary epithelial cell line, NMuMG. Here we show that HAdV-2 gene expression and progeny formation in NMuMG cells transformed with the SV40 T antigen (NMuMG-T cells) were as efficient as in the parental NMuMG cells. Injection of HAdV-2 into tumours established by NMuMG-T in SCID mice caused reduced tumour growth and signs of intratumoural lesions. HAdV-2 replicated within the NMuMG-T-established tumours, but not in interspersed host-derived tissues within the tumours. The specific infection of NMuMG-T-derived tumours was verified by the lack of viral DNA in kidney, lung or spleen although low levels of viral DNA was occasionally found in liver.

Keywords
Oncolytic adenovirus, Murine cells, Anti-tumour activity, Permissive infection, Viral replication
National Category
Infectious Medicine
Identifiers
urn:nbn:se:uu:diva-282389 (URN)10.1016/j.virol.2015.11.031 (DOI)000370892100005 ()26707269 (PubMedID)
Funder
Swedish Cancer Society
Available from: 2016-04-05 Created: 2016-04-05 Last updated: 2017-11-30Bibliographically approved
Retamal, J., Borges, J. B., Bruhn, A., Cao, X., Feinstein, R., Hedenstierna, G., . . . Larsson, A. (2016). High respiratory rate is associated with early reduction of lung edema clearance in an experimental model of ARDS. Acta Anaesthesiologica Scandinavica, 60(1), 79-92
Open this publication in new window or tab >>High respiratory rate is associated with early reduction of lung edema clearance in an experimental model of ARDS
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2016 (English)In: Acta Anaesthesiologica Scandinavica, ISSN 0001-5172, E-ISSN 1399-6576, Vol. 60, no 1, p. 79-92Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: The independent impact of respiratory rate on ventilator-induced lung injury has not been fully elucidated. The aim of this study was to investigate the effects of two clinically relevant respiratory rates on early ventilator-induced lung injury evolution and lung edema during the protective ARDSNet strategy. We hypothesized that the use of a higher respiratory rate during a protective ARDSNet ventilation strategy increases lung inflammation and, in addition, lung edema associated to strain-induced activation of transforming growth factor beta (TGF-β) in the lung epithelium.

METHODS: Twelve healthy piglets were submitted to a two-hit lung injury model and randomized into two groups: LRR (20 breaths/min) and HRR (40 breaths/min). They were mechanically ventilated during 6 h according to the ARDSNet strategy. We assessed respiratory mechanics, hemodynamics, and extravascular lung water (EVLW). At the end of the experiment, the lungs were excised and wet/dry ratio, TGF-β pathway markers, regional histology, and cytokines were evaluated.

RESULTS: No differences in oxygenation, PaCO2 levels, systemic and pulmonary arterial pressures were observed during the study. Respiratory system compliance and mean airway pressure were lower in LRR group. A decrease in EVLW over time occurred only in the LRR group (P < 0.05). Wet/dry ratio was higher in the HRR group (P < 0.05), as well as TGF-β pathway activation. Histological findings suggestive of inflammation and inflammatory tissue cytokines were higher in LRR.

CONCLUSION: HRR was associated with more pulmonary edema and higher activation of the TGF-β pathway. In contrast with our hypothesis, HRR was associated with less lung inflammation.

National Category
Anesthesiology and Intensive Care
Research subject
Anaesthesiology and Intensive Care
Identifiers
urn:nbn:se:uu:diva-264211 (URN)10.1111/aas.12596 (DOI)000368139400010 ()26256848 (PubMedID)
Funder
Swedish Heart Lung FoundationSwedish Research Council, K2015-99X-22731-01-4
Available from: 2015-10-07 Created: 2015-10-07 Last updated: 2017-12-01Bibliographically approved
Kamranvar, S. A., Gupta, D. K., Huang, Y., Gupta, R. K. & Johansson, S. (2016). Integrin signaling via FAK-Src controls cytokinetic abscission by decelerating PLK1 degradation and subsequent recruitment of CEP55 at the midbody. OncoTarget, 7(21), 30820-30830
Open this publication in new window or tab >>Integrin signaling via FAK-Src controls cytokinetic abscission by decelerating PLK1 degradation and subsequent recruitment of CEP55 at the midbody
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2016 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 21, p. 30820-30830Article in journal (Refereed) Published
Abstract [en]

Adhesion to extracellular matrix is required for cell cycle progression through the G1 phase and for the completion of cytokinesis in normal adherent cells. Cancer cells acquire the ability to proliferate anchorage-independently, a characteristic feature of malignantly transformed cells. However, the molecular mechanisms underlying this escape of the normal control mechanisms remain unclear. The current study aimed to identify adhesion-induced reactions regulating the cytokinesis of non-transformed human fibroblasts. The adhesion-dependent control of cytokinesis was found to occur at a late stage close to the abscission, during which the endosomal sorting complex required for transport (ESCRT) severs the thin intercellular bridge connecting two nascent daughter cells. CEP55, a key protein involved in the abscission process, was localized at the midbody in both adherent and non-adherent fibroblasts, but it was unable to efficiently recruit ALIX, TSG101, and consequently the ESCRT-III subunit CHMP4B was missing in the non-adherent cells. PLK1, a kinase that prevents premature recruitment of CEP55 to the midbody, disappeared from this site more rapidly in the non-adherent cells. A FAK-Src signaling pathway downstream of integrin-mediated cell adhesion was found to decelerate both PLK1 degradation and CEP55 accumulation at the midbody. These data identify the regulation of PLK1 and CEP55 as steps where integrins exert control over the cytokinetic abscission.

Keywords
cytokinesis, CEP55, PLK1, integrin, FAK
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-299793 (URN)10.18632/oncotarget.9003 (DOI)000377746600074 ()
Funder
Swedish Cancer Society
Available from: 2016-07-28 Created: 2016-07-27 Last updated: 2018-12-04Bibliographically approved
Roche, F., Sipilä, K., Honjo, S., Staffan, J., Tugues, S., Heino, J. & Claesson-Welsh, L. (2015). Histidine-rich glycoprotein blocks collagen-binding integrins and adhesion of endothelial cells through low-affinity interaction with alpha 2 integrin. Matrix Biology, 48, 89-99
Open this publication in new window or tab >>Histidine-rich glycoprotein blocks collagen-binding integrins and adhesion of endothelial cells through low-affinity interaction with alpha 2 integrin
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2015 (English)In: Matrix Biology, ISSN 0945-053X, E-ISSN 1569-1802, Vol. 48, p. 89-99Article in journal (Refereed) Published
Abstract [en]

The plasma protein histidine-rich glycoprotein (HRG) affects the morphology and function of both endothelial cells (ECs) and monocytes/macrophages in cancer. Here, we examined the mechanism of action of HRG's effect on ECs. HRG suppressed adhesion, spreading and migration of ECs specifically on collagen I (COL I) whereas ECs seeded on other extracellular matrix proteins were insensitive to HRG. HRG did not bind specifically to COL I or to the α-integrin binding site on collagen, GFOGER. Furthermore, HRG's inhibition of EC adhesion was not dependent upon heparan sulfate (HS) moieties as heparitinase-treated ECs remained sensitive to HRG. C2C12 cells expressing α2 integrin, the major collagen-binding α-integrin subunit in ECs, showed increased binding of HRG compared with wild type C2C12 cells lacking the α2 subunit. Recombinant α2 I-domain protein bound HRG and to a higher extent when in active conformation. However, the α2 I-domain bound weakly to HRG compared with COL I and the purified α2β1 ectodomain complex failed to retain HRG. We conclude that HRG binds to α2 integrin through low-affinity interactions in a HS-independent manner, thereby blocking EC-adhesion to COL I.

Keywords
HRG; Adhesion; Integrin; Endothelial cells; Collagen
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-273699 (URN)10.1016/j.matbio.2015.06.002 (DOI)000366617000009 ()26051322 (PubMedID)
Funder
Swedish Research CouncilSwedish Cancer SocietyKnut and Alice Wallenberg Foundation
Available from: 2016-01-17 Created: 2016-01-17 Last updated: 2018-01-10Bibliographically approved
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