uu.seUppsala University Publications
Change search
Link to record
Permanent link

Direct link
BETA
Nelander, Sven
Publications (10 of 37) Show all publications
Mega, A., Hartmark Nilsen, M., Leiss, L. W., Tobin, N. P., Miletic, H., Sleire, L., . . . Östman, A. (2020). Astrocytes enhance glioblastoma growth.. Glia, 68(2), 316-327
Open this publication in new window or tab >>Astrocytes enhance glioblastoma growth.
Show others...
2020 (English)In: Glia, ISSN 0894-1491, E-ISSN 1098-1136, Vol. 68, no 2, p. 316-327Article in journal (Refereed) Published
Abstract [en]

Glioblastoma (GBM) is a deadly disease with a need for deeper understanding and new therapeutic approaches. The microenvironment of glioblastoma has previously been shown to guide glioblastoma progression. In this study, astrocytes were investigated with regard to their effect on glioblastoma proliferation through correlative analyses of clinical samples and experimental in vitro and in vivo studies. Co-culture techniques were used to investigate the GBM growth enhancing potential of astrocytes. Cell sorting and RNA sequencing were used to generate a GBM-associated astrocyte signature and to investigate astrocyte-induced GBM genes. A NOD scid GBM mouse model was used for in vivo studies. A gene signature reflecting GBM-activated astrocytes was associated with poor prognosis in the TCGA GBM dataset. Two genes, periostin and serglycin, induced in GBM cells upon exposure to astrocytes were expressed at higher levels in cases with high "astrocyte signature score". Astrocytes were shown to enhance glioblastoma cell growth in cell lines and in a patient-derived culture, in a manner dependent on cell-cell contact and involving increased cell proliferation. Furthermore, co-injection of astrocytes with glioblastoma cells reduced survival in an orthotopic GBM model in NOD scid mice. In conclusion, this study suggests that astrocytes contribute to glioblastoma growth and implies this crosstalk as a candidate target for novel therapies.

Keywords
astrocytes, glioblastoma, glioma, microenvironment, proliferation
National Category
Medical Biotechnology Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-399954 (URN)10.1002/glia.23718 (DOI)31509308 (PubMedID)
Available from: 2019-12-17 Created: 2019-12-17 Last updated: 2020-02-17Bibliographically approved
Weishaupt, H., Johansson, P., Sundström, A., Lubovac-Pilav, Z., Olsson, B., Nelander, S. & Johansson Swartling, F. K. (2019). Batch-normalization of cerebellar and medulloblastoma gene expression datasets utilizing empirically defined negative control genes. Bioinformatics, 35(18), 3357-3364
Open this publication in new window or tab >>Batch-normalization of cerebellar and medulloblastoma gene expression datasets utilizing empirically defined negative control genes
Show others...
2019 (English)In: Bioinformatics, ISSN 1367-4803, E-ISSN 1367-4811, Vol. 35, no 18, p. 3357-3364Article in journal (Refereed) Published
Abstract [en]

Motivation: Medulloblastoma (MB) is a brain cancer predominantly arising in children. Roughly 70% of patients are cured today, but survivors often suffer from severe sequelae. MB has been extensively studied by molecular profiling, but often in small and scattered cohorts. To improve cure rates and reduce treatment side effects, accurate integration of such data to increase analytical power will be important, if not essential.

Results: We have integrated 23 transcription datasets, spanning 1350 MB and 291 normal brain samples. To remove batch effects, we combined the Removal of Unwanted Variation (RUV) method with a novel pipeline for determining empirical negative control genes and a panel of metrics to evaluate normalization performance. The documented approach enabled the removal of a majority of batch effects, producing a large-scale, integrative dataset of MB and cerebellar expression data. The proposed strategy will be broadly applicable for accurate integration of data and incorporation of normal reference samples for studies of various diseases. We hope that the integrated dataset will improve current research in the field of MB by allowing more large-scale gene expression analyses.

Place, publisher, year, edition, pages
OXFORD UNIV PRESS, 2019
National Category
Bioinformatics (Computational Biology)
Identifiers
urn:nbn:se:uu:diva-395689 (URN)10.1093/bioinformatics/btz066 (DOI)000487327500019 ()30715209 (PubMedID)
Funder
EU, European Research Council, 640275Swedish Cancer SocietySwedish Research CouncilSwedish Childhood Cancer FoundationRagnar Söderbergs stiftelse
Available from: 2019-10-24 Created: 2019-10-24 Last updated: 2019-10-24Bibliographically approved
Cancer, M., Drews, L. F., Bengtsson, J., Bolin, S., Rosén, G., Westermark, B., . . . Johansson, F. K. (2019). BET and Aurora Kinase A inhibitors synergize against MYCN-positive human glioblastoma cells. Cell Death and Disease, 10, Article ID 881.
Open this publication in new window or tab >>BET and Aurora Kinase A inhibitors synergize against MYCN-positive human glioblastoma cells
Show others...
2019 (English)In: Cell Death and Disease, ISSN 2041-4889, E-ISSN 2041-4889, Vol. 10, article id 881Article in journal (Refereed) Published
Abstract [en]

Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults. Patients usually undergo surgery followed by aggressive radio- and chemotherapy with the alkylating agent temozolomide (TMZ). Still, median survival is only 12-15 months after diagnosis. Many human cancers including GBMs demonstrate addiction to MYC transcription factor signaling and can become susceptible to inhibition of MYC downstream genes. JQ1 is an effective inhibitor of BET Bromodomains, a class of epigenetic readers regulating expression of downstream MYC targets. Here, we show that BET inhibition decreases viability of patient-derived GBM cell lines. We propose a distinct expression signature of MYCN-elevated GBM cells that correlates with significant sensitivity to BET inhibition. In tumors showing JQ1 sensitivity, we found enrichment of pathways regulating cell cycle, DNA damage response and repair. As DNA repair leads to acquired chemoresistance to TMZ, JQ1 treatment in combination with TMZ synergistically inhibited proliferation of MYCN-elevated cells. Bioinformatic analyses further showed that the expression of MYCN correlates with Aurora Kinase A levels and Aurora Kinase inhibitors indeed showed synergistic efficacy in combination with BET inhibition. Collectively, our data suggest that BET inhibitors could potentiate the efficacy of either TMZ or Aurora Kinase inhibitors in GBM treatment.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2019
National Category
Cancer and Oncology Cell Biology
Identifiers
urn:nbn:se:uu:diva-398423 (URN)10.1038/s41419-019-2120-1 (DOI)000497973200005 ()31754113 (PubMedID)
Funder
Swedish Cancer SocietySwedish Research CouncilSwedish Society of MedicineRagnar Söderbergs stiftelseSwedish Childhood Cancer FoundationScience for Life Laboratory - a national resource center for high-throughput molecular bioscience
Available from: 2019-12-06 Created: 2019-12-06 Last updated: 2019-12-06Bibliographically approved
Kaffes, I., Szulzewsky, F., Chen, Z., Herting, C. J., Gabanic, B., Vega, J. E. V., . . . Hambardzumyan, D. (2019). Human Mesenchymal glioblastomas are characterized by an increased immune cell presence compared to Proneural and Classical tumors. Oncoimmunology, 8(11)
Open this publication in new window or tab >>Human Mesenchymal glioblastomas are characterized by an increased immune cell presence compared to Proneural and Classical tumors
Show others...
2019 (English)In: Oncoimmunology, ISSN 2162-4011, E-ISSN 2162-402X, Vol. 8, no 11Article in journal (Refereed) Published
Abstract [en]

Glioblastoma (GBM) is the most aggressive malignant primary brain tumor in adults, with a median survival of 14.6 months. Recent efforts have focused on identifying clinically relevant subgroups to improve our understanding of pathogenetic mechanisms and patient stratification. Concurrently, the role of immune cells in the tumor microenvironment has received increasing attention, especially T cells and tumor-associated macrophages (TAM). The latter are a mixed population of activated brain-resident microglia and infiltrating monocytes/monocyte-derived macrophages, both of which express ionized calcium-binding adapter molecule 1 (IBA1). This study investigated differences in immune cell subpopulations among distinct transcriptional subtypes of GBM. Human GBM samples were molecularly characterized and assigned to Proneural, Mesenchymal or Classical subtypes as defined by NanoString nCounter Technology. Subsequently, we performed and analyzed automated immunohistochemical stainings for TAM as well as specific T cell populations. The Mesenchymal subtype of GBM showed the highest presence of TAM, CD8(+), CD3(+) and FOXP3(+) T cells, as compared to Proneural and Classical subtypes. High expression levels of the TAM-related gene AIF1, which encodes the TAM-specific protein IBA1, correlated with a worse prognosis in Proneural GBM, but conferred a survival benefit in Mesenchymal tumors. We used our data to construct a mathematical model that could reliably identify Mesenchymal GBM with high sensitivity using a combination of the aforementioned cell-specific IHC markers. In conclusion, we demonstrated that molecularly distinct GBM subtypes are characterized by profound differences in the composition of their immune microenvironment, which could potentially help to identify tumors amenable to immunotherapy.

Place, publisher, year, edition, pages
TAYLOR & FRANCIS INC, 2019
Keywords
Glioblastoma, microenvironment, subtype, macrophage, T cell, AIF1
National Category
Cell and Molecular Biology Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-396107 (URN)10.1080/2162402X.2019.1655360 (DOI)000483119600001 ()31646100 (PubMedID)
Funder
Swedish Cancer Society, 110363Swedish Cancer Society, 140385Swedish Cancer Society, 130500Swedish Research Council, 521-2013-3356German Research Foundation (DFG), SZ 350/1-1
Available from: 2019-11-01 Created: 2019-11-01 Last updated: 2019-11-01Bibliographically approved
Nelander, S. (2019). Increasing the accuracy of glioblastoma subtypes: Factoring in the tumor's cell of origin. MOLECULAR & CELLULAR ONCOLOGY, 6(1), Article ID e1302907.
Open this publication in new window or tab >>Increasing the accuracy of glioblastoma subtypes: Factoring in the tumor's cell of origin
2019 (English)In: MOLECULAR & CELLULAR ONCOLOGY, ISSN 2372-3556, Vol. 6, no 1, article id e1302907Article in journal (Refereed) Published
Abstract [en]

The transcriptional classification of glioblastoma has proven to be a complex issue. In the absence of strong correlations between underlying genomic lesions and transcriptional subtype, there is a need to systematically understand the origins of the glioblastoma subtypes. A recent integrated analysis of data from both mouse models and patient-derived cells supports that the glioblastoma's cell of origin is important in shaping transcriptional diversity and tumor cell malignancy.

Keywords
Cell of origin, data integration, glioblastoma classification, plasticity, systems biology
National Category
Cancer and Oncology Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-388041 (URN)10.1080/23723556.2017.1302907 (DOI)000470299200001 ()30788413 (PubMedID)
Available from: 2019-06-27 Created: 2019-06-27 Last updated: 2019-06-27Bibliographically approved
Thoren, M. M., Masoumi, K. C., Krona, C., Huang, X., Kundu, S., Schmidt, L., . . . Lundgren-Åkerlund, E. (2019). Integrin alpha 10, a Novel Therapeutic Target in Glioblastoma, Regulates Cell Migration, Proliferation, and Survival. Cancers, 11(4), Article ID 587.
Open this publication in new window or tab >>Integrin alpha 10, a Novel Therapeutic Target in Glioblastoma, Regulates Cell Migration, Proliferation, and Survival
Show others...
2019 (English)In: Cancers, ISSN 2072-6694, Vol. 11, no 4, article id 587Article in journal (Refereed) Published
Abstract [en]

New, effective treatment strategies for glioblastomas (GBMs), the most malignant and invasive brain tumors in adults, are highly needed. In this study, we investigated the potential of integrin alpha 10 beta 1 as a therapeutic target in GBMs. Expression levels and the role of integrin alpha 10 beta 1 were studied in patient-derived GBM tissues and cell lines. The effect of an antibody-drug conjugate (ADC), an integrin alpha 10 antibody conjugated to saporin, on GBM cells and in a xenograft mouse model was studied. We found that integrin alpha 10 beta 1 was strongly expressed in both GBM tissues and cells, whereas morphologically unaffected brain tissues showed only minor expression. Partial or no overlap was seen with integrins alpha 3, alpha 6, and alpha 7, known to be expressed in GBM. Further analysis of a subpopulation of GBM cells selected for high integrin alpha 10 expression demonstrated increased proliferation and sphere formation. Additionally, siRNA-mediated knockdown of integrin alpha 10 in GBM cells led to decreased migration and increased cell death. Furthermore, the ADC reduced viability and sphere formation of GBM cells and induced cell death both in vitro and in vivo. Our results demonstrate that integrin alpha 10 beta 1 has a functional role in GBM cells and is a novel, potential therapeutic target for the treatment of GBM.

Place, publisher, year, edition, pages
MDPI, 2019
Keywords
glioblastoma (GBM), glioma, integrin alpha 10, antibody-drug conjugate (ADC), saporin
National Category
Cell Biology
Identifiers
urn:nbn:se:uu:diva-385567 (URN)10.3390/cancers11040587 (DOI)000467773400155 ()31027305 (PubMedID)
Available from: 2019-06-19 Created: 2019-06-19 Last updated: 2019-06-19Bibliographically approved
Xie, Y., Sundström, A., Maturi, N. P., Tan, E.-J., Marinescu, V. D., Jarvius, M., . . . Uhrbom, L. (2019). LGR5 promotes tumorigenicity and invasion of glioblastoma stem-like cells and is a potential therapeutic target for a subset of glioblastoma patients. Journal of Pathology, 247(2), 228-240
Open this publication in new window or tab >>LGR5 promotes tumorigenicity and invasion of glioblastoma stem-like cells and is a potential therapeutic target for a subset of glioblastoma patients
Show others...
2019 (English)In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 247, no 2, p. 228-240Article in journal (Refereed) Published
Abstract [en]

Glioblastoma (GBM) is the most common and lethal primary malignant brain tumor which lacks efficient treatment and predictive biomarkers. Expression of the epithelial stem cell marker Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) has been described in GBM, but its functional role has not been conclusively elucidated. Here, we have investigated the role of LGR5 in a large repository of patient-derived GBM stem cell (GSC) cultures. The consequences of LGR5 overexpression or depletion have been analyzed using in vitro and in vivo methods, which showed that, among those with highest LGR5 expression (LGR5(high)), there were two phenotypically distinct groups: one that was dependent on LGR5 for its malignant properties and another that was unaffected by changes in LGR5 expression. The LGR5-responding cultures could be identified by their significantly higher self-renewal capacity as measured by extreme limiting dilution assay (ELDA), and these LGR5(high)-ELDA(high) cultures were also significantly more malignant and invasive compared to the LGR5(high)-ELDA(low) cultures. This showed that LGR5 expression alone would not be a strict marker of LGR5 responsiveness. In a search for additional biomarkers, we identified LPAR4, CCND2, and OLIG2 that were significantly upregulated in LGR5-responsive GSC cultures, and we found that OLIG2 together with LGR5 were predictive of GSC radiation and drug response. Overall, we show that LGR5 regulates the malignant phenotype in a subset of patient-derived GSC cultures, which supports its potential as a predictive GBM biomarker. Copyright (c) 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Place, publisher, year, edition, pages
John Wiley & Sons, 2019
Keywords
glioblastoma stem-like cells, LGR5, self-renewal, invasion, radiation response
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-376723 (URN)10.1002/path.5186 (DOI)000456331900009 ()30357839 (PubMedID)
Funder
Swedish Research Council, 2012-02591Swedish Cancer Society, 2012/4882015/656
Available from: 2019-02-11 Created: 2019-02-11 Last updated: 2019-02-11Bibliographically approved
Matuszewski, D. J., Wählby, C., Krona, C., Nelander, S. & Sintorn, I.-M. (2018). Image-Based Detection of Patient-Specific Drug-Induced Cell-Cycle Effects in Glioblastoma. SLAS Discovery: Advancing Life Sciences R&D, 23(10), 1030-1039
Open this publication in new window or tab >>Image-Based Detection of Patient-Specific Drug-Induced Cell-Cycle Effects in Glioblastoma
Show others...
2018 (English)In: SLAS Discovery: Advancing Life Sciences R&D, ISSN 2472-5552, Vol. 23, no 10, p. 1030-1039Article in journal (Refereed) Published
Abstract [en]

Image-based analysis is an increasingly important tool to characterize the effect of drugs in large-scale chemical screens. Herein, we present image and data analysis methods to investigate population cell-cycle dynamics in patient-derived brain tumor cells. Images of glioblastoma cells grown in multiwell plates were used to extract per-cell descriptors, including nuclear DNA content. We reduced the DNA content data from per-cell descriptors to per-well frequency distributions, which were used to identify compounds affecting cell-cycle phase distribution. We analyzed cells from 15 patient cases representing multiple subtypes of glioblastoma and searched for clusters of cell-cycle phase distributions characterizing similarities in response to 249 compounds at 11 doses. We show that this approach applied in a blind analysis with unlabeled substances identified drugs that are commonly used for treating solid tumors as well as other compounds that are well known for inducing cell-cycle arrest. Redistribution of nuclear DNA content signals is thus a robust metric of cell-cycle arrest in patient-derived glioblastoma cells.

National Category
Computer Vision and Robotics (Autonomous Systems)
Research subject
Computerized Image Processing
Identifiers
urn:nbn:se:uu:diva-368698 (URN)10.1177/2472555218791414 (DOI)000452283500003 ()30074852 (PubMedID)
Funder
AstraZenecaSwedish Research Council, 2012-4968; 2014-6075eSSENCE - An eScience Collaboration
Available from: 2018-12-06 Created: 2018-12-06 Last updated: 2019-10-09Bibliographically approved
Baskaran, S., Mayrhofer, M., Göransson Kultima, H., Bergström, T., Elfineh, L., Cavelier, L., . . . Nelander, S. (2018). Primary glioblastoma cells for precision medicine: a quantitative portrait of genomic (in)stability during the first 30 passages. Neuro-Oncology, 20(8), 1080-1091
Open this publication in new window or tab >>Primary glioblastoma cells for precision medicine: a quantitative portrait of genomic (in)stability during the first 30 passages
Show others...
2018 (English)In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 20, no 8, p. 1080-1091Article in journal (Refereed) Published
Abstract [en]

Background: Primary glioblastoma cell (GC) cultures have emerged as a key model in brain tumor research, with the potential to uncover patient-specific differences in therapy response. However, there is limited quantitative information about the stability of such cells during the initial 20-30 passages of culture.

Methods: We interrogated 3 patient-derived GC cultures at dense time intervals during the first 30 passages of culture. Combining state-of-the-art signal processing methods with a mathematical model of growth, we estimated clonal composition, rates of change, affected pathways, and correlations between altered gene dosage and transcription.

Results: We demonstrate that GC cultures undergo sequential clonal takeovers, observed through variable proportions of specific subchromosomal lesions, variations in aneuploid cell content, and variations in subpopulation cell cycling times. The GC cultures also show significant transcriptional drift in several metabolic and signaling pathways, including ribosomal synthesis, telomere packaging and signaling via the mammalian target of rapamycin, Wnt, and interferon pathways, to a high degree explained by changes in gene dosage. In addition to these adaptations, the cultured GCs showed signs of shifting transcriptional subtype. Compared with chromosomal aberrations and gene expression, DNA methylations remained comparatively stable during passaging, and may be favorable as a biomarker.

Conclusion: Taken together, GC cultures undergo significant genomic and transcriptional changes that need to be considered in functional experiments and biomarker studies that involve primary glioblastoma cells.

Place, publisher, year, edition, pages
OXFORD UNIV PRESS INC, 2018
Keywords
aneuploidy, clones, GBM DNA methylation, GBM subtype, glioma stem cell cultures, patient derived GBM cell cultures, systems biology
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-361042 (URN)10.1093/neuonc/noy024 (DOI)000438338000009 ()29462414 (PubMedID)
Funder
Swedish Research Council, 2014-03314Swedish Cancer Society, CAN 2017/628Swedish Foundation for Strategic Research , BD15-088
Available from: 2018-09-20 Created: 2018-09-20 Last updated: 2018-09-20Bibliographically approved
Heiland, D. H., Ferrarese, R., Claus, R., Dai, F., Masilamani, A. P., Kling, E., . . . Carro, M. S. (2017). c-Jun-N-terminal phosphorylation regulates DNMT1 expression and genome wide methylation in gliomas. OncoTarget, 8(4), 6940-6954
Open this publication in new window or tab >>c-Jun-N-terminal phosphorylation regulates DNMT1 expression and genome wide methylation in gliomas
Show others...
2017 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 4, p. 6940-6954Article in journal (Refereed) Published
Abstract [en]

High-grade gliomas (HGG) are the most common brain tumors, with an average survival time of 14 months. A glioma-CpG island methylator phenotype (G-CIMP), associated with better clinical outcome, has been described in low and high-grade gliomas. Mutation of IDH1 is known to drive the G-CIMP status. In some cases, however, the hypermethylation phenotype is independent of IDH1 mutation, suggesting the involvement of other mechanisms. Here, we demonstrate that DNMT1 expression is higher in low-grade gliomas compared to glioblastomas and correlates with phosphorylated c-Jun. We show that phospho-c-Jun binds to the DNMT1 promoter and causes DNA hypermethylation. Phospho-c-Jun activation by Anisomycin treatment in primary glioblastoma-derived cells attenuates the aggressive features of mesenchymal glioblastomas and leads to promoter methylation and downregulation of key mesenchymal genes (CD44, MMP9 and CHI3L1). Our findings suggest that phospho-c-Jun activates an important regulatory mechanism to control DNMT1 expression and regulate global DNA methylation in Glioblastoma.

Keywords
Glioblastoma, G-CIMP, DNMT1, p-c-Jun, mesenchymal
National Category
Cancer and Oncology Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-317698 (URN)10.18632/oncotarget.14330 (DOI)000393289000125 ()28036297 (PubMedID)
Funder
German Research Foundation (DFG), CA 1246/2-1
Available from: 2017-03-17 Created: 2017-03-17 Last updated: 2018-01-13Bibliographically approved
Organisations

Search in DiVA

Show all publications