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Westermark, Bengt
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Publications (10 of 73) Show all publications
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
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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
Heldin, C.-H., Lennartsson, J. & Westermark, B. (2018). Involvement of platelet-derived growth factor ligands and receptors in tumorigenesis. Journal of Internal Medicine, 283(1), 16-44
Open this publication in new window or tab >>Involvement of platelet-derived growth factor ligands and receptors in tumorigenesis
2018 (English)In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 283, no 1, p. 16-44Article, review/survey (Refereed) Published
Abstract [en]

Platelet-derived growth factor (PDGF) isoforms and their receptors have important roles during embryogenesis, particularly in the development of various mesenchymal cell types in different organs. In the adult, PDGF stimulates wound healing and regulates tissue homeostasis. However, overactivity of PDGF signalling is associated with malignancies and other diseases characterized by excessive cell proliferation, such as fibrotic conditions and atherosclerosis. In certain tumours, genetic or epigenetic alterations of the genes for PDGF ligands and receptors drive tumour cell proliferation and survival. Examples include the rare skin tumour dermatofibrosarcoma protuberance, which is driven by autocrine PDGF stimulation due to translocation of a PDGF gene, and certain gastrointestinal stromal tumours and leukaemias, which are driven by constitute activation of PDGF receptors due to point mutations and formation of fusion proteins ofthe receptors, respectively. Moreover, PDGF stimulates cells in tumour stroma and promotes angiogenesis as well as the development of cancer-associated fibroblasts, both of which promote tumour progression. Inhibitors of PDGF signalling may thus be of clinical usefulness in the treatment of certain tumours.

Keywords
inhibitor, kinase, malignancy, receptor, signal transduction, PDGF
National Category
Cell and Molecular Biology Cell Biology
Identifiers
urn:nbn:se:uu:diva-347709 (URN)10.1111/joim.12690 (DOI)000418411100002 ()28940884 (PubMedID)
Funder
Swedish Cancer Society, 2016/445; 2015/226; 2014/468Swedish Research Council, 2015-02757
Available from: 2018-04-06 Created: 2018-04-06 Last updated: 2018-04-06Bibliographically approved
Glimelius, B., Melin, B., Enblad, G., Alafuzoff, I., Beskow, A. H., Ahlström, H., . . . Sjöblom, T. (2018). U-CAN: a prospective longitudinal collection of biomaterials and clinical information from adult cancer patients in Sweden.. Acta Oncologica, 57(2), 187-194
Open this publication in new window or tab >>U-CAN: a prospective longitudinal collection of biomaterials and clinical information from adult cancer patients in Sweden.
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2018 (English)In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 57, no 2, p. 187-194Article in journal (Refereed) Published
Abstract [en]

Background: Progress in cancer biomarker discovery is dependent on access to high-quality biological materials and high-resolution clinical data from the same cases. To overcome current limitations, a systematic prospective longitudinal sampling of multidisciplinary clinical data, blood and tissue from cancer patients was therefore initiated in 2010 by Uppsala and Umeå Universities and involving their corresponding University Hospitals, which are referral centers for one third of the Swedish population.

Material and Methods: Patients with cancer of selected types who are treated at one of the participating hospitals are eligible for inclusion. The healthcare-integrated sampling scheme encompasses clinical data, questionnaires, blood, fresh frozen and formalin-fixed paraffin-embedded tissue specimens, diagnostic slides and radiology bioimaging data.

Results: In this ongoing effort, 12,265 patients with brain tumors, breast cancers, colorectal cancers, gynecological cancers, hematological malignancies, lung cancers, neuroendocrine tumors or prostate cancers have been included until the end of 2016. From the 6914 patients included during the first five years, 98% were sampled for blood at diagnosis, 83% had paraffin-embedded and 58% had fresh frozen tissues collected. For Uppsala County, 55% of all cancer patients were included in the cohort.

Conclusions: Close collaboration between participating hospitals and universities enabled prospective, longitudinal biobanking of blood and tissues and collection of multidisciplinary clinical data from cancer patients in the U-CAN cohort. Here, we summarize the first five years of operations, present U-CAN as a highly valuable cohort that will contribute to enhanced cancer research and describe the procedures to access samples and data.

National Category
Cancer and Oncology Urology and Nephrology Clinical Laboratory Medicine
Research subject
Pathology
Identifiers
urn:nbn:se:uu:diva-325565 (URN)10.1080/0284186X.2017.1337926 (DOI)000423473200003 ()28631533 (PubMedID)
Funder
Swedish Cancer Society
Available from: 2017-06-26 Created: 2017-06-26 Last updated: 2019-03-29Bibliographically approved
Attarha, S., Roy, A., Westermark, B. & Tchougounova, E. (2017). Mast cells modulate proliferation, migration and sternness of glioma cells through downregulation of GSK3 beta expression and inhibition of STAT3 activation. Cellular Signalling, 37, 81-92
Open this publication in new window or tab >>Mast cells modulate proliferation, migration and sternness of glioma cells through downregulation of GSK3 beta expression and inhibition of STAT3 activation
2017 (English)In: Cellular Signalling, ISSN 0898-6568, E-ISSN 1873-3913, Vol. 37, p. 81-92Article in journal (Refereed) Published
Abstract [en]

Glioblastoma (GBM) heterogeneity is the main obstacle to efficient treatment due to the existence of sub population of cells with increased tumorigenicity and network of tumor associated parenchymal cells in the tumor microenvironment. We previously demonstrated that mast cells (MCs) infiltrate mouse and human gliomas in response to variety of signals in a glioma grade-dependent manner. However, the role of MCs in glioma development and the mechanisms behind MCs-glioma cells interaction remain unidentified. In the present study, we show that MCs upon activation by glioma cells produce soluble factors including IL-6, which are documented to be involved in cancer-related activities. We observe 'tumor educated' MCs decrease glioma cell proliferation and migration, reduce self-renewal capacity and expression of stemness markers but in turn promote glioma cell differentiation. 'Tumor educated' MC derived mediators exert these effects via inactivation of STAT3 signaling pathway through GSK3 beta down-regulation. We identified 'tumor educated' MC derived IL-6 as one of the contributors among the complex mixture of MCs mediators, to be partially involved in the observed MC induced biological effect on glioma cells. Thus, MC mediated abolition of STAT3 signaling hampers glioma cell proliferation and migration by suppressing their stemness and inducing differentiation via down-regulation of GSK3 beta expression. Targeting newly identified inflammatory MC-STAT3 axis could contribute to patient tailored therapy and unveil potential future therapeutic opportunities for patients.

Keywords
Mast cell, Glioma, GSK3 beta, IL-6, STAT3
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-334406 (URN)10.1016/j.cellsig.2017.06.004 (DOI)000408784300008 ()28600192 (PubMedID)
Available from: 2017-11-23 Created: 2017-11-23 Last updated: 2018-01-13Bibliographically approved
Segerman, A., Niklasson, M., Haglund, C., Bergström, T., Jarvius, M., Xie, Y., . . . Westermark, B. (2016). Clonal Variation in Drug and Radiation Response among Glioma-Initiating Cells Is Linked to Proneural-Mesenchymal Transition. Cell reports, 17(11), 2994-3009
Open this publication in new window or tab >>Clonal Variation in Drug and Radiation Response among Glioma-Initiating Cells Is Linked to Proneural-Mesenchymal Transition
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2016 (English)In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 17, no 11, p. 2994-3009Article in journal (Refereed) Published
Abstract [en]

Intratumoral heterogeneity is a hallmark of glioblastoma multiforme and thought to negatively affect treatment efficacy. Here, we establish libraries of glioma-initiating cell (GIC) clones from patient samples and find extensive molecular and phenotypic variability among clones, including a range of responses to radiation and drugs. This widespread variability was observed as a continuumof multitherapy resistance phenotypes linked to a proneural-mesenchymal shift in the transcriptome. Multitherapy resistance was associated with a semi-stable cell state that was characterized by an altered DNA methylation pattern at promoter regions of mesenchymal master regulators and enhancers. The gradient of cell states within the GIC compartment constitutes a distinct form of heterogeneity. Our findings may open an avenue toward the development of new therapeutic rationales designed to reverse resistant cell states.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-314416 (URN)10.1016/j.celrep.2016.11.056 (DOI)000390894700019 ()
Funder
Knut and Alice Wallenberg Foundation, 2013.0280Swedish Cancer Society, 150670
Available from: 2017-02-08 Created: 2017-02-02 Last updated: 2017-11-29Bibliographically approved
Agarwal, P., Enroth, S., Teichmann, M., Jernberg Wiklund, H., Smit, A., Westermark, B. & Singh, U. (2016). Growth signals employ CGGBP1 to suppress transcription of Alu-SINEs. Cell Cycle, 15(12), 1558-1571
Open this publication in new window or tab >>Growth signals employ CGGBP1 to suppress transcription of Alu-SINEs
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2016 (English)In: Cell Cycle, ISSN 1538-4101, E-ISSN 1551-4005, Vol. 15, no 12, p. 1558-1571Article in journal (Refereed) Published
Abstract [en]

CGGBP1 (CGG triplet repeat-binding protein 1) regulates cell proliferation, stress response,cytokinesis, telomeric integrity and transcription. It could affect these processes by modulatingtarget gene expression under different conditions. Identification of CGGBP1-target genes andtheir regulation could reveal how a transcription regulator affects such diverse cellular processes.Here we describe the mechanisms of differential gene expression regulation by CGGBP1 inquiescent or growing cells. By studying global gene expression patterns and genome-wide DNAbindingpatterns of CGGBP1, we show that a possible mechanism through which it affects theexpression of RNA Pol II-transcribed genes in trans depends on Alu RNA. We also show that itregulates Alu transcription in cis by binding to Alu promoter. Our results also indicate thatpotential phosphorylation of CGGBP1 upon growth stimulation facilitates its nuclear retention,Alu-binding and dislodging of RNA Pol III therefrom. These findings provide insights into howAlu transcription is regulated in response to growth signals.

Keywords
Alu-SINEs; CGGBP1; ChIP-seq; growth signals; RNA Pol III; transcription; tyrosine phosphorylation
National Category
Cell Biology
Research subject
Bioinformatics; Biology
Identifiers
urn:nbn:se:uu:diva-230959 (URN)10.4161/15384101.2014.967094 (DOI)000379743800011 ()25483050 (PubMedID)
Funder
Swedish Cancer SocietySwedish Research Council
Available from: 2014-09-01 Created: 2014-09-01 Last updated: 2017-12-05Bibliographically approved
Darmanis, S., Gallant, C. J., Marinescu, V. D., Niklasson, M., Segerman, A., Flamourakis, G., . . . Landegren, U. (2016). Simultaneous Multiplexed Measurement of RNA and Proteins in Single Cells. Cell reports, 14(2), 380-389
Open this publication in new window or tab >>Simultaneous Multiplexed Measurement of RNA and Proteins in Single Cells
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2016 (English)In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 14, no 2, p. 380-389Article in journal (Refereed) Published
Abstract [en]

Significant advances have been made in methods to analyze genomes and transcriptomes of single cells, but to fully define cell states, proteins must also be accessed as central actors defining a cell's phenotype. Methods currently used to analyze endogenous protein expression in single cells are limited in specificity, throughput, or multiplex capability. Here, we present an approach to simultaneously and specifically interrogate large sets of protein and RNA targets in lysates from individual cells, enabling investigations of cell functions and responses. We applied our method to investigate the effects of BMP4, an experimental therapeutic agent, on early-passage glioblastoma cell cultures. We uncovered significant heterogeneity in responses to treatment at levels of RNA and protein, with a subset of cells reacting in a distinct manner to BMP4. Moreover, we found overall poor correlation between protein and RNA at the level of single cells, with proteins more accurately defining responses to treatment.

National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-276810 (URN)10.1016/j.celrep.2015.12.021 (DOI)000368101600020 ()26748716 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme, 259796EU, FP7, Seventh Framework Programme, 294409Swedish Research CouncilKnut and Alice Wallenberg FoundationSwedish Cancer Society
Available from: 2016-02-16 Created: 2016-02-16 Last updated: 2018-01-10Bibliographically approved
Agarwal, P., Collier, P., Fritz, M.-Y. H., Benes, V., Wiklund, H. J., Westermark, B. & Singh, U. (2015). CGGBP1 mitigates cytosine methylation at repetitive DNA sequences. BMC Genomics, 16, Article ID 390.
Open this publication in new window or tab >>CGGBP1 mitigates cytosine methylation at repetitive DNA sequences
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2015 (English)In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 16, article id 390Article in journal (Refereed) Published
Abstract [en]

Background: CGGBP1 is a repetitive DNA-binding transcription regulator with target sites at CpG-rich sequences such as CGG repeats and Alu-SINEs and L1-LINEs. The role of CGGBP1 as a possible mediator of CpG methylation however remains unknown. At CpG-rich sequences cytosine methylation is a major mechanism of transcriptional repression. Concordantly, gene-rich regions typically carry lower levels of CpG methylation than the repetitive elements. It is well known that at interspersed repeats Alu-SINEs and L1-LINEs high levels of CpG methylation constitute a transcriptional silencing and retrotransposon inactivating mechanism. Results: Here, we have studied genome-wide CpG methylation with or without CGGBP1-depletion. By high throughput sequencing of bisulfite-treated genomic DNA we have identified CGGBP1 to be a negative regulator of CpG methylation at repetitive DNA sequences. In addition, we have studied CpG methylation alterations on Alu and L1 retrotransposons in CGGBP1-depleted cells using a novel bisulfite-treatment and high throughput sequencing approach. Conclusions: The results clearly show that CGGBP1 is a possible bidirectional regulator of CpG methylation at Alus, and acts as a repressor of methylation at L1 retrotransposons.

National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-256126 (URN)10.1186/s12864-015-1593-2 (DOI)000354528700001 ()25981527 (PubMedID)
Available from: 2015-06-22 Created: 2015-06-22 Last updated: 2018-01-11Bibliographically approved
Singh, U. & Westermark, B. (2015). CGGBP1-an indispensable protein with ubiquitous cytoprotective functions. Upsala Journal of Medical Sciences, 120(4), 219-232
Open this publication in new window or tab >>CGGBP1-an indispensable protein with ubiquitous cytoprotective functions
2015 (English)In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 120, no 4, p. 219-232Article, review/survey (Refereed) Published
Abstract [en]

The human genome contains multiple stretches of CGG trinucleotide repeats, which act as transcription- and translation-regulatory elements but at the same time form secondary structures that impede replication and give rise to sites of chromosome fragility. Proteins binding to such DNA elements may be involved in divergent cellular processes such as transcription, DNA damage, and epigenetic state of the chromatin. We review here the work done on CGG repeats and associated proteins with special focus on a factor called CGGBP1. CGGBP1 presents with an interesting example of factors that do not have any single dedicated function, but participate indispensably in multiple processes. Both experimental results and data from cancer genome sequencing have revealed that any alteration in CGGBP1 that compromises its function is not tolerated by normal or cancer cells alike. Based upon a large amount of published data, information from databases, and unpublished results, we decipher in this review how CGGBP1 is a classic example of the one factor, divergent functions' paradigm of cytoprotection. By taking cues from the studies on CGGBP1, more such factors can be discovered for a better understanding of the evolution of mechanisms of cellular survival.

Keywords
Brain tumours, molecular biology, oncogenes
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-276107 (URN)10.3109/03009734.2015.1086451 (DOI)000365684900001 ()26482656 (PubMedID)
Funder
Swedish Cancer SocietySwedish Research Council
Available from: 2016-02-09 Created: 2016-02-09 Last updated: 2017-11-30Bibliographically approved
Babateen, O., Jin, Z., Bhandage, A. K., Korol, S. V., Westermark, B., Forsberg Nilsson, K., . . . Birnir, B. (2015). Etomidate, propofol and diazepam potentiate GABA-evoked GABAA currents in a cell line derived from Human glioblastoma. European Journal of Pharmacology, 748, 101-107
Open this publication in new window or tab >>Etomidate, propofol and diazepam potentiate GABA-evoked GABAA currents in a cell line derived from Human glioblastoma
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2015 (English)In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 748, p. 101-107Article in journal (Refereed) Published
Abstract [en]

GABAA receptors are pentameric chloride ion channels that are opened by GABA. We have screened a cell line derived from human glioblastoma, U3047MG, for expression of GABAA receptor subunit isoforms and formation of functional ion channels. We identified GABAA receptors subunit α2, α3, α5, β1, β2, β3, δ, γ3, π, and θ mRNAs in the U3047MG cell line. Whole-cell GABA-activated currents were recorded and the half-maximal concentration (EC50) for the GABA-activated current was 36μM. The currents were activated by THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol) and enhanced by the benzodiazepine diazepam (1μM) and the general anesthetics etomidate and propofol (50μM). In line with the expressed GABAA receptors containing at least the α3β3θ subunits, the receptors were highly sensitive to etomidate (EC50=55nM). Immunocytochemistry identified expression of the α3 and β3 subunit proteins. Our results show that the GABAA receptors in the glial cell line are functional and are modulated by classical GABAA receptor drugs. We propose that the U3047MG cell line may be used as a model system to study GABAA receptors function and pharmacology in glial cells.

National Category
Basic Medicine
Identifiers
urn:nbn:se:uu:diva-239191 (URN)10.1016/j.ejphar.2014.12.001 (DOI)000348840500013 ()25510230 (PubMedID)
Available from: 2014-12-19 Created: 2014-12-19 Last updated: 2018-01-11
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